Hepatitis C, Chronic

Essentials of Diagnosis

• Chronic inflammatory reaction of the liver of more than 3–6 months' duration

• Persistently abnormal serum aminotransferase levels and antibody to hepatitis C virus (HCV) in serum

General Considerations

• Chronic hepatitis is characterized on

  • The basis of the etiology

  • The grade of portal, periportal, and lobular inflammation (minimal, mild, moderate, or severe)

  • The stage of fibrosis (none, mild, moderate, severe, cirrhosis)

• HCV may be the most common etiology of chronic hepatitis

• HCV coinfection is found in 30% of persons infected with HIV

• Anti-HCV is not protective; in chronic hepatitis its presence in serum signifies that HCV is the cause

Demographics

• Chronic hepatitis C develops in up to 85% of patients with acute hepatitis C

• Worldwide, 170 million people are infected with HCV, with 1.8% of the US population infected

Symptoms and Signs

• Clinically indistinguishable from chronic hepatitis due to other causes

Differential Diagnosis

• Hepatitis B and D (delta agent)

• Autoimmune hepatitis

• Alcoholic and nonalcoholic steatohepatitis

• α₁-Antiprotease deficiency

• Drug-induced hepatitis

• Hemochromatosis

• Wilson disease

• Gluten enteropathy (rarely)

Laboratory Tests

• Serum anti-HCV by enzyme immunoassay (EIA) is present (Figure 16–3)

• In approximately 40% of cases, serum aminotransferase levels are persistently normal

• In rare cases of negative anti-HCV EIA, HCV RNA is detected by polymerase chain reaction (PCR)

Diagnostic Procedures

• Liver biopsy is indicated in patients offered treatment for diagnosis, staging, and predicting response to therapy

Medications

• Peginterferon and ribavirin

  • Combination of these agents was standard therapy from the late 1990s to the early 2010s

  • Ribavirin continues to be used in some all-oral regimens but use is declining

• Because of high discontinuation rates and distressing side effects, peginterferon-based treatment is being supplanted by new oral direct-acting antiviral agents (Table 16–6)

  • Nonstructural (NS)3/4A protease inhibitors

    • Higher rates of response were achieved in persons infected with HCV genotype 1 when a NS3/4A serine protease inhibitor was added to peginterferon plus ribavirin

  • NS5A inhibitors

    • Characterized by high antiviral potency at picomolar doses

  • NS5B nucleos(t)ide polymerase inhibitors

    • Active against all HCV genotypes

    • Have a high barrier to resistance

  • NS5B non-nucleos(t)ide polymerase inhibitors

    • Non-nucleoside polymerase inhibitors are the weakest class of compounds against HCV because of a low barrier to resistance

    • Most drugs in this class are more active against HCV genotype 1b than HCV genotype 1a

    • Being developed to be used only in combination with the other direct-acting antiviral agents, mainly protease inhibitors and NS5A inhibitors

• Simeprevir

  • Effective for genotypes 1 and 4

  • Dosage: 150 mg orally once daily

  • Used in combination with pegylated interferon and ribavirin or with sofosbuvir

• Paritaprevir

  • Effective for genotypes 1 and 4

  • Dosage: 150 mg orally once daily

  • Used in combination with ombitasavir and dasabuvir; ritonavir (100 mg) boosted

  • Used with ribavirin for genotype 1b with cirrhosis and for genotype 1a

  • Used in combination with ombitasavir, ritonavir boosting, and ritonavir for genotype 4

• Grazoprevir

  • Effective for genotypes 1, 4, 5, and 6

  • Dosage: 100 mg orally once daily

  • Used in combination with elbasvir 50 mg orally daily for HCV genotypes 1, 4, and 6

• Glecaprevir

  • Effective against genotypes 1–6

  • Dosage: 200–300 mg orally once daily

  • Used in combination with pibrentasvir with or without ribavirin

  • Glecaprevir and pibrentasvir is given for 8 weeks for genotypes 1–6

• Voxilaprevir

  • Effective against genotypes 1–6

  • Dosage: 100 mg orally once daily

  • Used in combination with sofosbuvir and velpatasvir

• Asunaprevir

  • Effective against genotypes 1 and 4

  • Dosage: 200 mg orally twice daily

  • Not approved in United States

• Daclatasvir

  • Effective against genotypes 1–6

  • Dosage: 60 mg orally once daily

  • Used in combination with sofosbuvir (with or without ribavirin) depending on presence of cirrhosis

  • Used in combination with pegylated interferon and ribavirin for genotype 4

  • Use in combination with asunaprevir (with or without beclabuvir) is under study

• Ledipasvir

  • Has potent activity against genotypes 1, 4, 5, and 6

  • Dosage: 90 mg orally once daily

  • Has been formulated in combination with sofosbuvir (400 mg once daily) (marketed as Harvoni)

    • Highly effective in both treatment-naive and treatment-experienced patients, even those with cirrhosis

    • In treatment-naive patients without cirrhosis, the duration of treatment can be shortened to 8 weeks if the baseline HCV RNA level is < 6 million international units/mL

    • Sustained virologic response rates are well above 90%, including patients coinfected with HIV

    • Regimen has emerged as a first-line therapy for HCV genotype 1

• Ombitasvir

  • Effective against genotypes 1 and 4

  • Dosage: 25 mg orally once daily

  • Used in combination with paritaprevir (ritonavir boosted) with or without dasabuvir and with or without ritonavir

• Elbasvir

  • Effective against genotypes 1, 4, and 6

  • Dosage: 50 mg orally daily in combination with grazoprevir 100 mg

• Velpatasvir

  • Effective against genotypes 1–6

  • Dosage: 100 mg orally once daily

  • Used in combination with sofosbuvir (marketed as Epclusa); may be used with sofosbuvir and voxilaprevir

  • Sofosbuvir and velpatasvir is given for 12 weeks for genotypes 1, 2, 4, 5, or 6

• Pibrentasvir

  • Effective against genotypes 1–6

  • Dosage: 120 mg orally once daily

  • Used in combination with glecaprevir with or without ribavirin

• Sofosbuvir

  • Effective against genotypes 1–6

  • Dosage: 400 mg orally once daily

  • For all genotypes:

    • Used with pegylated interferon and ribavirin

    • Used with daclatasvir

    • Used in combination with velpatasvir (marketed as Epclusa)

    • Used with velpatasvir and voxilaprevir

  • For genotypes 2 and 3: Use with ribavirin

  • For genotypes 1 and 4: Use with simeprevir

  • For genotypes 1, 3, and 4: Use with ledipasvir

• Dasabuvir

  • Effective against genotypes 1 and 4

  • Dosage: 250 mg orally twice daily

  • Used in combination with paritaprevir, boosted by ritonavir

  • Used in combination with ombitasavir with or without ribavirin

• Beclabuvir

  • Effective against genotype 1

  • Dosage: 75 mg orally twice daily

  • Use in combination with daclatasvir and asunaprevir is under study

  • Not available in United States

• Boceprevir

  • Used in combination with pegylated interferon and ribavirin

  • No longer marketed in United States

• Telaprevir

  • Used in combination with pegylated interferon and ribavirin

  • No longer marketed in United States

Complications

• The following may be related to chronic hepatitis C

  • Cryoglobulinemia

  • Membranoproliferative glomerulonephritis

  • Lichen planus

  • Autoimmune thyroiditis

  • Lymphocytic sialadenitis

  • Idiopathic pulmonary fibrosis

  • Porphyria cutanea tarda

  • Non-Hodgkin lymphoma

  • Monoclonal gammopathy

Prognosis

• HCV genotype 1 has become easy to cure with oral direct-acting agents, with expected sustained virologic response rates above 90%

• Virtually all HCV genotype 2 infection is curable with all-oral regimens

• HCV genotype 3 infection, particularly in association with cirrhosis, remains the most challenging to treat

• Up to 80% of cases of acute hepatitis C becomes chronic hepatitis, which in many individuals progresses very slowly

• Most patients with persistently normal serum aminotransferase levels have mild chronic hepatitis with slow or absent progression to cirrhosis

• However, cirrhosis is present in 10% of these patients

• Progression to cirrhosis occurs in 20% of affected patients after 20 years, with an increased risk in men, those who drink more than 50 g of alcohol daily, and possibly those who acquire HCV infection after age 40

• Immunosuppressed persons (eg, those with hypogammaglobulinemia, HIV infection and a low CD4 count, or organ transplantation on immunosuppressants) progress more rapidly to cirrhosis than immunocompetent persons

• Hepatocellular carcinoma

  • Develops in cirrhosis at a rate of 3–5% per year

  • Patients with HCV genotype 1b are at higher risk than those with other genotypes

• Antiviral therapy

  • Probably improves survival and quality of life

  • Is costly but cost-effective

  • Retards and even reverses fibrosis

  • May reduce the risk of hepatocellular carcinoma in responders

• HCV infection, especially that treated with antiviral therapy, appears to be associated with increased cardiovascular mortality, especially in persons with diabetes mellitus and hypertension

• Long-term morbidity and mortality

  • Lower in black than in white patients

  • Lowest in those infected with HCV genotype 2

  • Highest in those with HCV genotype 3

• An increased risk of death from extrahepatic cancers has been described

• Although mortality from cirrhosis and hepatocellular carcinoma due to hepatitis C is still substantial, the need for liver transplantation for chronic hepatitis C is declining, and survival after transplantation is improving

Prevention

• Strict isolation of patients is not necessary, but hand washing after bowel movements is required

• Thorough hand washing by anyone who may contact contaminated utensils, bedding, or clothing is essential

• Testing of donated blood for HCV has helped reduce the risk of transfusion-associated hepatitis C from 10% in the past to about 1 in 2 million units today

When to Refer

• For liver biopsy

• For antiviral therapy

When to Admit

• For complications of decompensated cirrhosis