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Hepatitis C, Chronic

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Hepatitis C, Chronic

By Anna E. Rutherford, MD, MPH

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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

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Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Treatment is with direct-acting antiviral drugs and other agents depending on genotype; permanent elimination of detectable viral RNA is possible.

(See also Causes of Hepatitis, Overview of Chronic Hepatitis, and Acute Hepatitis C.)

Hepatitis lasting > 6 mo is generally defined as chronic hepatitis, although this duration is arbitrary.

There are 6 major genotypes of hepatitis C virus (HCV), which vary in their response to treatment. Genotype 1 is more common than genotypes 2, 3, 4, 5, and 6; it accounts for 70 to 80% of cases of chronic hepatitis C in the US.

Acute hepatitis C becomes chronic in about 75% of patients. The Centers for Disease Control and Prevention (CDC) estimates that about 2.8 million people in the US have chronic hepatitis C infection. Chronic hepatitis C progresses to cirrhosis in 20 to 30% of patients; cirrhosis often takes decades to appear. Hepatocellular carcinoma can result from HCV-induced cirrhosis but results only rarely from chronic infection without cirrhosis (unlike in HBV infection).

Clinical Calculator: Cirrhosis Probability in Hepatitis C

Symptoms and Signs

Many patients are asymptomatic and do not have jaundice, although some have malaise, anorexia, fatigue, and nonspecific upper abdominal discomfort. Often, the first findings are signs of chronic liver disease (eg, splenomegaly, spider nevi, palmar erythema) or complications of cirrhosis (eg, portal hypertension, ascites, encephalopathy).

Chronic hepatitis C is occasionally associated with lichen planus, mucocutaneous vasculitis, glomerulonephritis, porphyria cutanea tarda, and, perhaps, non-Hodgkin B-cell lymphoma.

Diagnosis

  • Serologic testing

The diagnosis of chronic hepatitis C is suspected in patients with suggestive symptoms and signs, incidentally noted elevations in aminotransferase levels, or previously diagnosed acute hepatitis.

Diagnosis is confirmed by finding positive anti-HCV and positive HCV-RNA ≥ 6 mo after initial infection (see Table: Hepatitis C Serology).

Hepatitis C Serology

Marker

Acute HCV Infection

Chronic HCV Infection

Prior HCV Infection*

Anti-HCV

+

+

+

HCV-RNA

+

+

−

*Patients have had HCV infection and spontaneously recovered or been successfully treated.

Anti-HCV = antibody to HCV; HCV = hepatitis C virus.

Liver biopsy is useful for one or more of the following:

  • Grading inflammatory activity

  • Staging fibrosis or progression of disease (which can sometimes help determine which patients to treat and when)

  • Excluding other causes of liver disease

However, the role of liver biopsy is evolving in hepatitis C, and biopsy is being supplanted by noninvasive imaging (eg, ultrasound elastography, magnetic resonance elastography) and serum markers of fibrosis, as well as scoring systems for fibrosis based on serologic markers.

HCV genotype is determined before treatment because genotype influences the course, duration, and success of treatment.

HCV-RNA detection and quantification is used to help diagnose hepatitis C and to evaluate treatment response during and after treatment. For most currently available quantitative HCV-RNA assays, the lower limit of detection is at least < 50 IU/mL. If a quantitative assay does not have that level of sensitivity, a qualitative assay can be used. Qualitative assays can detect very low levels of HCV-RNA, often as low as < 10 IU/mL, and provide results as positive or negative. Qualitative tests can be used to confirm a diagnosis of hepatitis C or a sustained virologic response (SVR), defined as no detectable HCV-RNA at 12 and 24 wk after completion of treatment, depending on the drug regimen used.

(See also the American Association for the Study of Liver Disease’s practice guideline Diagnosis, Management, and Treatment of Hepatitis C and the U.S. Preventive Services Task Force’s clinical guideline Screening for Hepatitis C in Adults.)

Other tests

Liver function tests are needed if not previously done; they include serum ALT, AST, alkaline phosphatase, and bilirubin.

Other tests should be done to evaluate disease severity; they include serum albumin, platelet count, and PT/INR.

Patients should be tested for HIV and hepatitis B infection because transmission of these infections is similar.

If symptoms or signs of cryoglobulinemia develop during chronic hepatitis C, cryoglobulin levels and rheumatoid factor should be measured; high levels of rheumatoid factor and low levels of complement suggest cryoglobulinemia.

Screening for complications

Patients with chronic HCV infection and advanced fibrosis or cirrhosis should be screened every 6 mo for hepatocellular cancer with ultrasonography and serum alpha-fetoprotein measurement, although the cost-effectiveness of this practice is debated.

Prognosis

Prognosis depends on whether patients have an SVR (ie, no detectable HCV-RNA at 12 and 24 wk after completion of treatment, depending on the drug regimen used).

Patients who have an SVR have a > 99% chance of remaining HCV RNA–negative and are typically considered cured. Nearly 95% of patients with an SVR have improved histologic findings, including fibrosis and histologic activity index; in addition, risk of progression to cirrhosis, hepatic failure, and liver-related death is reduced. In patients who have cirrhosis and portal hypertension and who were treated with interferon-based regimens, an SVR has been shown to reduce portal pressures and significantly reduce risk of hepatic decompensation, liver-related death, all-cause mortality, and hepatocellular carcinoma (1).

Achieving an SVR with interferon-based therapies is more likely when ≥ 1 of the following are present:

  • Genotype other than genotype 1

  • Low pretreatment viral loads

  • Age < 40 yr

  • Body weight < 75 kg

  • No bridging fibrosis or cirrhosis

  • Ethnicity other than African American

  • No hepatic steatosis or insulin resistance

Likelihood of achieving an SVR with new interferon-free regimens seems to depend mostly on the following:

  • Pretreatment viral load

  • Degree of liver fibrosis

  • Response to prior treatment

Prognosis reference

  • 1. van der Meer AJ, Veldt BJ, Feld JJ, et al: Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 308(24):2584–2593, 2012.

Treatment

  • Direct-acting antiviral drugs

  • Sometimes with pegylated interferon (IFN) and/or ribavirin

Overview of HCV treatment

(See also the American Association for the Study of Liver Disease’s [AASLD] practice guidelines Recommendations for Testing, Managing, and Treating Hepatitis C and the AASLD/Infectious Disease Society of America guidelines When and in Whom to Initiate HCV Therapy.)

For chronic hepatitis C, treatment is indicated if both of the following are present:

  • Aminotransferase levels are elevated.

  • Biopsy shows active inflammatory disease with evolving fibrosis.

The goal of treatment is permanent elimination of HCV-RNA (ie, SVR), which is associated with permanent normalization of aminotransferase and cessation of histologic progression. Treatment results are more favorable in patients with moderate fibrosis and a viral load of < 600,000 to 800,000 IU/mL than in patients with cirrhosis and a viral load of > 800,000 IU/mL.

Until late 2013, all genotypes were treated with pegylated IFN-alpha plus ribavirin. Now, most patients are treated with antiviral drugs (direct-acting antivirals [DAAs]) that affect specific HCV targets, such as proteases or polymerases (see also Hepatitis C, Chronic : HCV genotype 1 and Hepatitis C, Chronic : HCV genotypes 2, 3, 4, 5, and 6).

DAAs used to treat HCV include

  • Telaprevir and boceprevir: 1st-generation protease inhibitors with activity against HCV genotype 1

  • Simeprevir: A 2nd-generation genotype 1–specific protease inhibitor

  • Sofosbuvir: A polymerase inhibitor with activity against HCV genotypes 1 to 6

  • Paritaprevir: A protease inhibitor

  • Ledipasvir: A protease inhibitor

  • Dasabuvir: A polymerase inhibitor

  • Ombitasvir: An inhibitor of the viral nonstructural protein 5A (NS5A inhibitor)

  • Daclatasvir: An NS5A inhibitor

  • Elbasvir: An NS5A inhibitor

  • Grazoprevir: A protease inhibitor

Telaprevir, boceprevir, and simeprevir are given with pegylated IFN and ribavirin.

Sofosbuvir can be used without interferon; it can be given with ribavirin (for genotypes 1 to 6), simeprevir (for genotype 1), or daclatasvir (for genotypes 1 to 3) in all-oral regimens. Ledipasvir and sofosbuvir are available in a single pill to treat HCV genotypes 1, 4, and 6. Elbasvir/grazoprevir in a single pill is used to treat HCV genotypes 1 and 4.

The following 5-drug regimen is effective against genotypes 1 and 4:

  • Paritaprevir/ritonavir/ombitasvir (in a single pill) given once/day

  • Dasabuvir, given twice/day

  • Ribavirin, given twice/day

Paritaprevir/ritonavir/ombitasvir plus dasabuvir are available in a single package.

Ritonavir increases levels of paritaprevir but has no direct antiviral activity. Ribavirin is often used with DAAs.

Because more and more DAAs are being developed, current recommendations for HCV treatment are evolving rapidly. Recommendations for Testing, Managing, and Treating Hepatitis C from the American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA), available online, are updated frequently.

Decompensated cirrhosis due to hepatitis C is the most common indication for liver transplantation in the US. HCV recurs almost universally in the graft, and both patient and graft survival are less favorable than when transplantation is done for other indications. Many DAAs and interferon-free regimens are being used in patients who have hepatitis C and have received a liver transplant. When DAAs are used, the SVR rate in patients who have had a liver transplant exceeds 95% whether they have cirrhosis or not.

HCV genotype 1

Genotype 1 is more resistant to treatment with dual therapy with pegylated IFN-alpha plus ribavirin than other genotypes. Doing one of the following can increase the rate of SVR from < 50% (with dual therapy) to up to 95%:

  • Adding a protease inhibitor (telaprevir, boceprevir, or simeprevir) or polymerase inhibitor (sofosbuvir) to pegylated IFN-alpha plus ribavirin

  • Using an interferon-free regimen (eg, simeprevir or daclatasvir plus sofosbuvir; ledipasvir/sofosbuvir or elbasvir/grazoprevir; the 5-drug regimen of paritaprevir/ritonavir/ombitasvir, dasabuvir, and ribavirin) as first-line treatment

Pegylated IFN alpha-2b 1.5 mcg/kg sc once/wk and pegylated IFN alpha-2a 180 mcg sc once/wk have comparable results. Adverse effects of pegylated IFN-alpha are similar to those of IFN-alpha but may be less severe; contraindications are also similar (see above). Interferons are no longer recommended as first-line treatment for hepatitis C.

For ribavirin, dosage is 500 to 600 mg po bid. Ribavirin is usually well-tolerated but commonly causes anemia due to hemolysis; dosage should be decreased if hemoglobin decreases to < 10 g/dL. Ribavirin is teratogenic in both men and women, requiring contraception during treatment and for 6 mo after treatment is completed. Patients who cannot tolerate ribavirin should still be given pegylated IFN-alpha, but not using ribavirin reduces the likelihood of successful treatment. Ribavirin monotherapy is of no value.

First-line treatments for HCV genotype 1 include

  • Fixed-dose combination of ledipasvir 90 mg/sofosbuvir 400 mg po once/day for 8 to 24 wk depending on history of prior treatment, pretreatment viral load, and degree of liver fibrosis

  • Fixed-dose combination of elbasvir 50 mg/grazoprevir 100 mg po once/day with or without ribavirin 500 to 600 mg po bid for 12 to 16 wk depending on history of prior treatment, degree of liver fibrosis, and, in patients with genotype 1a, the presence or absence of baseline NS5A resistance–associated variants to elbasvir

  • Fixed-dose combination of paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg once/day plus dasabuvir 250 mg po bid and ribavirin 500 to 600 mg po bid for 12 to 24 wk depending on degree of liver fibrosis

  • Sofosbuvir 400 mg po once/day plus simeprevir 150 mg po once/day with or without ribavirin 500 to 600 mg po bid for 12 to 24 wk, depending of degree of liver fibrosis

  • Sofosbuvir 400 mg po once/day plus daclatasvir 60 mg once/day with or without ribavirin 500 to 600 mg po bid for 12 to 24 wk, depending on degree of liver fibrosis and history of prior treatment

Simeprevir can cause anemia and photosensitivity. All protease inhibitors have drug-drug interactions.

HCV genotypes 2, 3, 4, 5, and 6

For genotype 2, one of the following combinations is recommended:

  • Sofosbuvir 400 mg po once/day plus ribavirin 500 to 600 mg po bid for 12 to 24 wk

  • Sofosbuvir 400 mg po once/day plus daclatasvir 60 mg po once/day for 12 to 24 wk, depending on the degree of liver fibrosis

For genotype 3, first-line treatments include

  • Sofosbuvir 400 mg po once/day plus daclatasvir 60 mg po once/day with or without ribavirin 500 to 600 mg po bid for 12 to 24 wk depending on degree of liver fibrosis

  • Sofosbuvir 400 mg po once/day plus ribavirin 500 to 600 mg po bid plus weekly pegylated IFN-alpha for 12 wk

For genotype 4, first-line treatments include

  • Ledipasvir 90 mg/sofosbuvir 400 mg po once/day for 12 wk

  • Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg po once/day plus ribavirin 500 to 600 mg po bid for 12 wk

  • Elbasvir 50 mg/grazoprevir 100 mg po once/day for 12 wk

For genotypes 5 and 6, first-line treatments include

  • Ledipasvir 90 mg/sofosbuvir 400 mg po once/day for 12 wk

  • Sofosbuvir 400 mg po once/day plus ribavirin 500 to 600 mg po bid plus weekly pegylated IFN-alpha for 12 wk

Key Points

  • Chronic hepatitis C infection develops in 75% of patients with acute infection and leads to cirrhosis in 20 to 30%; some patients with cirrhosis develop hepatocellular carcinoma.

  • Diagnosis is confirmed by finding positive anti-HCV and positive HCV-RNA; then do biopsy and determine genotype.

  • Treatment varies by genotype but includes use of one or more direct-acting antiviral drugs, sometimes with pegylated IFN and/or ribavirin.

  • New treatments can permanently eliminate HCV-RNA in many patients.

More Information

Last full review/revision July 2016 by Anna E. Rutherford, MD, MPH

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • ribavirin
    VIRAZOLE
  • ritonavir
    NORVIR
  • boceprevir
    VICTRELIS
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