Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive HCV RNA ≥ 6 months after initial infection. Treatment is with direct-acting antiviral medications; permanent elimination of detectable viral RNA is possible.
(See also Causes of Hepatitis, Overview of Chronic Hepatitis, and Acute Hepatitis C.)
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 United States.
Acute hepatitis C becomes chronic in about 75% of patients. The Centers of Disease Control and Prevention (CDC) estimates that, from 2013 to 2016, about 2.4 million people in the United States had 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 (3); 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 16% of patients with alcohol-related liver disease harbor HCV (4). 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 (4).
General references
1. Centers for Disease Control and Prevention (CDC): Hepatitis C Resources for Health Care Professionals. Accessed June 6, 2022.
2. World Health Organization (WHO): Hepatitis C. Accessed June 6, 2022.
3. World Health Organization (WHO) : Hepatitis C. Key Facts. Accessed June 17, 2024.
4. Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, et al: Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 22(4):1411-1420, 2016. doi: 10.3748/wjg.v22.i4.1411
Symptoms and Signs of Chronic Hepatitis C
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, cutaneous 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 for Chronic Hepatitis C
One-time, routine screening is recommended for all people ≥ 18 years old, regardless of risk factors.
One-time screening is recommended for people < 18 years old with the following characteristics (1):
Are currently using or have ever injected illicit drugs, even if only once or only in the distant past
Have used intranasal illicit drugs
Are men who have sex with men
Are currently or have ever been treated with long-term hemodialysis
Have percutaneous or parenteral exposures in an unregulated setting
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 or are starting preexposure prophylaxis (PrEP) for HIV
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 reference
1. American Association for the Study of Liver Disease (AALD) and the Infectious Disease Society of America (IDSA): HCV Testing and Linkage to Care. Accessed May 8, 2024.
Diagnosis of Chronic Hepatitis C
Serologic testing
HCV RNA
(See also the American Association for the Study of Liver Diseases [AASLD]–Infectious Diseases Society of America [IDSA] practice guideline Hepatitis C Guidance 2023 Update for Testing, Managing, and Treating Hepatitis C Virus Infection; and the U.S. Preventive Services Task Force’s clinical guideline Hepatitis C Virus Infection in Adolescents and Adults: 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).
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 rarely used in hepatitis C and has been 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 sometimes determined before treatment because genotype influences the course, duration, and success of treatment. However, most of the direct-acting antivirals are effective in treating HCV across the range of genotypes.
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 about < 12 to 15 IU/mL, depending on the assay. 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 weeks after completion of treatment.
Other tests
Liver tests are needed if not previously done; they include serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase.
Other tests should be done to evaluate liver function; they include serum albumin, bilirubin, 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.
Treatment of Chronic Hepatitis C
Direct-acting antivirals
Overview of HCV treatment
(See also the American Association for the Study of Liver Disease [AASLD]–Infectious Disease Society of America [IDSA] practice guidelines Recommendations for Testing, Managing, and Treating Hepatitis C and 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.
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 polymerase. See tables Direct Acting Antivirals to Treat HCV and DAA Combination Therapies for the Treatment of HCV.
Direct Acting Antivirals (DAAs) to Treat HCV
NS3-4A Protease Inhibitors ("-previr") | NS5A Inhibitors ("-asvir") | NS5B Inhibitors ("-buvir") |
|---|---|---|
Glecaprevir | Ledipasvir | |
Grazoprevir | Pibrentasvir | |
Voxilaprevir | Velpatasvir | |
Elbasvir |
DAAs are not used as single medications but are used in specific combinations to maximize efficacy.
DAA Combination Therapies for the Treatment of HCV
Direct Acting Antiviral Combination | Genotype | Duration of Treatment |
|---|---|---|
1, 4, 5, 6 | 8–24 weeks depending on patient population | |
1–6 | 12 weeks | |
1–6 | 8–16 weeks depending on patient population | |
1, 4 | 12–16 weeks depending on patient population | |
1–6 | 12 weeks |
Current recommendations for HCV treatment are evolving rapidly. Hepatitis C Guidance 2023 Update: AASLD–IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection available online, are updated frequently.
Decompensated cirrhosis due to hepatitis C is the most common indication for liver transplantation in the United States. HCV recurs almost universally in the graft. Before the use of DAAs, patient and graft survival was 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 HCV-positive organs is being done increasingly, particularly among recipients who are also HCV-positive, thus expanding the pool of potential donors. If the recipient and donor are HCV-positive, treatment can be postponed until after transplantation. As a result, an unnecessary pretransplantation course of treatment can be avoided.
Treatment of hepatitis C in patients with decompensated cirrhosis should be done in consultation with hepatologists, ideally in a liver transplantation center. HCV regimens that include protease inhibitors (those medications with the ending of -previr) 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.
Treatment references
1. Bourlière M, Gordon SC, Flamm SL, et alN Engl J Med 376 (22):2134-2146, 2017. doi: 10.1056/NEJMoa1613512
2. Asselah T, Kowdley KV, Zadeikis N, et alClin Gastroenterol Hepatol 16 (3):417-426, 2018. doi: 10.1016/j.cgh.2017.09.027
Prognosis for Chronic Hepatitis C
Prognosis depends on whether patients have a sustained virologic response (SVR), ie, no detectable HCV-RNA at 12 weeks after completion of treatment.
Patients who have an SVR have a > 99% chance of remaining HCV RNA–negative and are typically considered cured (1). 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 (2).
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
Prognosis references
1. Lynch EN, Russo FP: Outcomes and follow-up after hepatitis C eradication with direct-acting antivirals. J Clin Med 12(6):2195, 2023. doi: 10.3390/jcm12062195
2. 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. doi:10.1001/jama.2012.144878
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.
Direct-acting antivirals are effective treatment across most genotypes.
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
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection: Up-to-date, peer-reviewed, unbiased, evidence-based
When and In Whom To Initiate HCV Therapy: Exploration of the clinical benefits of curing hepatitis C and of treating fibrosis early, the importance of pretreatment assessment, and considerations in specific populations; overview of cost, reimbursement, and cost-effectiveness for hepatitis C treatment regimens
Hepatitis C Virus Infection in Adolescents and Adults Screening: Exploration of the importance of screening, assessment of risk, use of screening tests including intervals, and treatment; supporting evidence provided
