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Hepatitis C, Chronic

By

Sonal Kumar

, MD, MPH, Weill Cornell Medical College

Last full review/revision Oct 2019| Content last modified Oct 2019
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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; permanent elimination of detectable viral RNA is possible.

Hepatitis lasting > 6 months 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 of Disease Control and Prevention (CDC) estimates that about 2.4 million people in the US have chronic hepatitis C infection (1). Worldwide, 71 million people are estimated to have chronic hepatitis C (2).

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 chronic HBV infection).

Up to 20% of patients with alcoholic liver disease harbor HCV. The reasons for this high association are unclear because concomitant alcohol and drug use accounts for only a portion of cases. In these patients, HCV and alcohol act synergistically to worsen liver inflammation and fibrosis.

General references

  • 1. CDC: Hepatitis C Questions and Answers for Health Professionals. Accessed 9/4/19.

  • 2. World Health Organization: Hepatitis C. Accessed 9/4/19.

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 cirrhosis (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, mixed cryoglobulinemia, and, perhaps, non-Hodgkin B-cell lymphoma. Symptoms of cryoglobulinemia include fatigue, myalgias, arthralgias, neuropathy, glomerulonephritis, and rashes (urticaria, purpura, leukocytoclastic vasculitis); asymptomatic cryoglobulinemia is more common.

Screening

People with certain characteristics should be screened for hepatitis C, whether they have suggestive symptoms or not. One-time screening is recommended for people with the following characteristics (1, 2):

  • Were born between 1945 and 1965, regardless of country of birth

  • Are currently using or have ever injected illicit drugs, even if only once or only in the distant past

  • Have used intranasal illicit drugs

  • Were given clotting factor concentrates produced before 1987

  • Were given a blood transfusion or an organ transplant before July 1992

  • Are currently or have ever been treated with long-term hemodialysis

  • Have abnormal alanine aminotransferase (ALT) levels or unexplained chronic liver disease

  • Work in health care or public safety and were exposed to HCV-positive blood through a needlestick, other injury by a sharp object, or mucosal contact

  • Have HIV infection

  • Have ever been incarcerated

  • Are children born to HCV-infected women

Such testing is important because symptoms may not develop until the hepatitis C has extensively damaged the liver, years after the initial infection.

Screening references

Diagnosis

  • Serologic testing

  • HCV RNA

(See also the American Association for the Study of Liver Disease’s practice guideline HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C and the U.S. Preventive Services Task Force’s clinical guideline Hepatitis C: Screening.)

The diagnosis of chronic hepatitis C is suspected in patients with any of the following:

  • Suggestive symptoms and signs

  • Incidentally noted elevations in aminotransferase levels

  • Previously diagnosed acute hepatitis

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

Table
icon

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 weeks after completion of treatment, depending on the drug regimen used.

Other tests

Liver tests are needed if not previously done; they include serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin.

Other tests should be done to evaluate liver function; they include serum albumin, platelet count, and prothrombin time/international normalized ratio (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 months for hepatocellular cancer with ultrasonography and serum alpha-fetoprotein measurement, although the cost-effectiveness of this practice, particularly serum alpha-fetoprotein measurement, is debated.

Prognosis

Prognosis depends on whether patients have a sustained virologic response (SVR), ie, no detectable HCV-RNA at 12 and 24 weeks 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).

Likelihood of achieving an SVR with direct-acting antiviral regimens seems to depend mostly on the following:

  • Degree of liver fibrosis

  • Response to prior treatment

  • HCV genotype

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

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's [IDSA] When and in Whom to Initiate HCV Therapy.)

For chronic hepatitis C, treatment is recommended for all patients, except those with a short life expectancy due to comorbid conditions that cannot be remediated by HCV therapy, liver transplantation, or another directed therapy.

The goal of treatment is permanent elimination of HCV RNA (ie, SVR), which is associated with permanent normalization of aminotransferase levels and cessation of histologic progression. Treatment results are more favorable in patients with less fibrosis than in patients with cirrhosis.

Until late 2013, all genotypes were treated with pegylated interferon alfa plus ribavirin. Now, interferon-based treatment regimens are no longer used, and ribavirin is no longer considered first-line and is used only in certain alternative regimens. Currently, all patients are treated with direct-acting antivirals (DAAs) that affect specific HCV targets, such as proteases or polymerases (see also HCV genotype 1 and HCV genotypes 2,3, 4, 5, and 6).

Pearls & Pitfalls

  • Interferon-based treatment regimens are no longer used to treat chronic hepatitis C, and ribavirin is used only in certain alternative regimens.

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

  • Velpatasvir: An NS5A inhibitor used to treat all HCV genotypes

  • Glecaprevir: A protease inhibitor used to treat all HCV genotypes

  • Pibrentasvir: An NS5A inhibitor used to treat all HCV genotypes

  • Voxilaprevir: An NS3/4A protease inhibitor

DAAs are not used as single drugs but are used in specific combinations to maximize efficacy.

Sofosbuvir is given in combination with other drugs. The preferred combinations include

  • Ledipasvir in a single pill to treat HCV genotypes 1, 4, 5 and 6

  • Velpatasvir in a single pill to treat HCV genotypes 1 through 6

  • Velpatasvir and voxilaprevir in a single pill to treat HCV genotypes 1 through 6

Sofosbuvir can also be given with ribavirin (for genotypes 1 through 6), simeprevir (for genotype 1), or daclatasvir (for genotypes 1 through 3) in all-oral regimens, but these regimens are not preferred.

The single pill containing sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg orally once a day for 12 weeks is used for re-treatment of chronic HCV infection in adults who have genotype 1, 2, 3, 4, 5, or 6 and were previously treated with a regimen containing an NS5A inhibitor or who have genotype 1a or 3 and were previously treated with a regimen containing sofosbuvir without an NS5A inhibitor (1). This combination pill (sofosbuvir, velpatasvir, and voxilaprevir) is not recommended for patients with moderate or severe hepatic impairment, and no dosage can be recommended for patients with severe renal impairment.

Elbasvir/grazoprevir in a single pill is used to treat HCV genotypes 1 and 4.

Glecapravir and pibrentasvir are available in a single pill to treat HCV genotypes 1 through 6.

The following 5-drug regimen, although not preferred, is effective against genotypes 1 and 4:

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

  • Dasabuvir, given twice a day

  • Ribavirin, given twice a day

Paritaprevir/ritonavir/ombitasvir plus dasabuvir, although not preferred, is available in a single package for genotypes 1 and 4.

Ritonavir increases levels of paritaprevir but has no direct antiviral activity.

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. Before the use of DAAs, patient and graft survival were less favorable than when transplantation is done for other indications. However, when DAAs are used, the SVR rate in patients who have had a liver transplant exceeds 95% whether they have cirrhosis or not. Because SVR rates are so high, transplantation of hepatitis C–positive organs is being done increasingly, particularly among recipients who are also hepatitis C–positive, thus expanding the pool of potential donors. If the recipient and donor are hepatitis C–positive, treatment can be postponed until after transplantation. As a result, an unnecessary pretransplantation course of treatment can be avoided.

Regimens of elbasvir/grazoprevir or glecaprevir/pibrentasvir are now considered to have a good safety profile and are effective in patients with end-stage kidney disease, including dialysis patients.

Treatment of hepatitis C in patients with decompensated cirrhosis should be done in consultation with hepatologists, ideally in a liver transplant center. HCV regimens that include protease inhibitors should not be used in patients with decompensated cirrhosis because levels of protease inhibitors are increased in patients with hepatic dysfunction.

Hepatitis B reactivation resulting in liver failure and death has been reported during or after HCV treatment with DAAs. Therefore, all patients with hepatitis C being treated with DAAs should be checked for evidence of chronic or prior hepatitis B; tests should include all of the following:

  • Hepatitis B surface antigen (HBsAg)

  • Hepatitis B surface antibody (anti-HBs)

  • IgG antibody to hepatitis B core (IgG anti-HBc)

Patients with chronic hepatitis B or evidence of prior hepatitis B should be monitored for reactivation during and after HCV treatment, and HBV antiviral therapy should be considered during the course of HCV treatment.

HCV genotype 1

Genotype 1 is more resistant to traditional treatment with dual therapy with pegylated interferon-alpha plus ribavirin than other genotypes. However, now with the use of interferon-free regimens of direct-acting antivirals (DAAs), the rate of SVR has increased from < 50% to up to 95%.

First-line regimens for HCV genotype 1 include

  • Ledipasvir/sofosbuvir

  • Elbasvir/grazoprevir

  • Velpatasvir/sofosbuvir

  • Glecaprevir/pibrentasvir

Fixed-dose combination of ledipasvir 90 mg/sofosbuvir 400 mg is given orally once a day for 8 to 12 weeks depending on history of prior treatment, pretreatment viral load, and degree of liver fibrosis.

Fixed-dose combination of elbasvir 50 mg/grazoprevir 100 mg is given orally once a day, with or without ribavirin 500 to 600 mg orally twice a day, for 12 to 16 weeks 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 velpatasvir 100 mg/sofosbuvir 400 mg is given orally once a day for 12 weeks.

Fixed-dose combination of glecaprevir 300 mg/pibrentasvir 120 mg is given orally once a day for 8 to 16 weeks, depending on history of prior treatment and degree of liver fibrosis.

Alternative regimens for HCV genotype 1 include

  • 5-drug regimen using the fixed-dose combination of paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg once a day plus dasabuvir 250 mg orally twice a day and ribavirin 500 to 600 mg orally twice a day for 12 to 24 weeks depending on degree of liver fibrosis

  • Sofosbuvir 400 mg orally once a day plus simeprevir 150 mg orally once a day, with or without ribavirin 500 to 600 mg orally twice a day, for 12 to 24 weeks, depending of degree of liver fibrosis

  • Sofosbuvir 400 mg orally once a day plus daclatasvir 60 mg orally once a day, with or without ribavirin 500 to 600 mg orally twice a day, for 12 to 24 weeks, depending on degree of liver fibrosis and history of prior treatment

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

Ribavirin is usually well-tolerated but commonly causes anemia due to hemolysis; dosage should be decreased if hemoglobin decreases to < 10 g/dL (100 g/L). Ribavirin is teratogenic in both men and women, requiring contraception during treatment and for 6 months after treatment is completed.

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

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

  • Fixed-dose combination of sofosbuvir 400 mg/velpatasvir 100 mg once a day for 12 weeks

  • Fixed-dose combination of glecaprevir 300 mg/pibrentasvir 120 mg once a day for 8 to 12 weeks, depending on history of prior treatment and degree of liver fibrosis (2)

An alternative regimen for genotype 2 is

  • Sofosbuvir 400 mg orally once a day plus daclatasvir 60 mg orally once a day for 12 to 24 weeks, depending on the degree of liver fibrosis

For genotype 3, first-line treatments include

  • Fixed-dose combination of sofosbuvir 400 mg/velpatasvir 100 mg once a day for 12 weeks

  • Fixed-dose combination of glecaprevir 300 mg/pibrentasvir 120 mg once a day for 8 to 16 weeks, depending on history of prior treatment and degree of liver fibrosis

An alternative regimen for genotype 3 is

  • Sofosbuvir 400 mg orally once a day plus daclatasvir 60 mg orally once a day with or without ribavirin 500 to 600 mg orally twice a day for 12 to 24 weeks depending on degree of liver fibrosis

For genotype 4, first-line treatments include

  • Fixed dose combination of ledipasvir 90 mg/sofosbuvir 400 mg orally once a day for 12 weeks

  • Fixed dose combination of elbasvir 50 mg/grazoprevir 100 mg orally once a /ay for 12 weeks

  • Fixed-dose combination of velpatasvir 100 mg/sofosbuvir 400 mg once a day for 12 weeks

  • Fixed-dose combination of glecaprevir 300 mg/pibrentasvir 120 mg once a day for 8 to 12 weeks, depending on degree of liver fibrosis

An alternative regimen for genotype 4 is

  • Fixed dose combination of paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg orally once a day plus ribavirin 500 to 600 mg orally twice a day for 12 to 16 weeks

For genotypes 5 and 6, first-line treatments include

  • Fixed dose combination of ledipasvir 90 mg/sofosbuvir 400 mg orally once a day for 12 weeks

  • Fixed dose combination of velpatasvir 100 mg/sofosbuvir 400 mg once a day for 12 weeks

  • Fixed-dose combination of glecaprevir 300 mg/pibrentasvir 120 mg once a day for 8 to 12 weeks, depending on degree of liver fibrosis

Treatment references

  • 1. Bourlière M, Gordon SC, Flamm SL, et al: Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med 376 (22):2134-2146, 2017. doi: 10.1056/NEJMoa1613512.

  • 2. Asselah T, Kowdley KV, Zadeikis N, et al: Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol 16 (3):417–426, 2018. doi: 10.1016/j.cgh.2017.09.027. Epub 2017 Sep 22.

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 ribavirin.

  • Pegylated interferon is no longer recommended for treatment of chronic hepatitis C.

  • New treatments can permanently eliminate HCV RNA in > 95% of patients.

  • Patients with decompensated cirrhosis should be treated by hepatologists, and regimens containing protease inhibitors should not be used.

More Information

Drugs Mentioned In This Article

Drug Name Select Trade
Pibrentasvir
Glecaprevir
Ledipasvir
Simeprevir
Sofosbuvir
VICTRELIS
NORVIR
VIRAZOLE
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