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Last Updated: 7/1/2015  

Hepatitis C

Hepatitis C virus is a leading cause of chronic liver disease. Worldwide, an estimated 180 million people are infected. In the U.S., approximately 4.1 million persons are positive for anti-HCV antibody and 80% of these are estimated to be viremic.

Screening
  • Screen patients born between 1945 and 1965 at least once, and screen those who are at increased risk for hepatitis C periodically.

  • Screen patients with test for anti-HCV antibody by ELISA; if positive, perform HCV RNA testing to confirm active infection.

Diagnosis
  • Test patients with signs or symptoms of liver disease for hepatitis C using anti-HCV antibody by ELISA; if positive, perform HCV RNA testing to confirm active infection.

  • HCV RNA test should be performed if HCV infection is suspected but anti-HCV antibody test is negative in patients who are immunocompromised (e.g. chronic renal failure, HIV patients, and organ transplant recipients) or suspected of having acute HCV infection.

  • Consider other causes of acute or chronic liver disease when evaluating for HCV.

  • Consider other disease processes that may be complications of hepatitis C infection.

Therapy
  • Consider an appropriate regimen of antiviral drug therapy for patients with chronic hepatitis C.

  • Test for immunity to HAV and HBV infection, and vaccinate susceptible patients.

Patient Education
  • Educate patients about the following:

    • Advisability of discontinuing all alcohol use

    • Typically slow progression of liver disease in chronic hepatitis C in the absence of ongoing alcohol use or other risks for progression

    • Treatment associated side effects

    • Routes of HCV transmission and ways to avoid transmission

Ask all patients about current or past use of or experimentation with illicit drugs, especially by injection or intranasal routes. 
  • Advise patients who use illicit drugs to:

    • Be screened for viral hepatitis and HIV infection

    • Discontinue use

    • Enter a substance-abuse treatment program

    • Obtain hepatitis A and B vaccination

    • Consider participating in a needle-exchange and/or other harm-reduction program

  • Be sure that queries about present and past illicit drug use are nonjudgmental and nonconfrontational.

Evidence
  • A 2015 CDC guideline on sexually transmitted diseases covers general principles, special populations (including pregnancy, adolescents, and LGBT), and general discussion with recommended guidelines on treating each of the major STIs. The report includes a section on HCV as an emerging infection, including preventive measures (1).

  • A 2011 systematic review of interventions to prevent HCV in injection drug users included 26 studies. A variety of intervention types were studied, including behavioral interventions, substance abuse programs, needle access and disinfection, and multi-component interventions. Combined strategies were the most effective, reducing the risk for HCV seroconversion by 75% (pooled RR, 0.25 [CI, 0.07 to 0.83]) (2).

  • A U.S. population-based study used NHANES data from 1999 to 2002 to determine HCV prevalence and risk factors. The prevalence of HCV was 1.6%, with the highest prevalence among adults aged 40 to 49 (4.3%). Risk factors included history of injection drug use, more than 20 lifetime sexual partners, and blood transfusion before 1992 (3).

  • The National Hepatitis Screening Survey, a cross-sectional screening study, evaluated the presence of HCV in 14,000 patients from 40 centers across the U.S. The prevalence of HCV was 7%, and 3% of patients had both HCV and hepatitis B infection. Risk factors for HCV included intravenous drug use, blood transfusions, hemodialysis, and having sex with an intravenous drug user (4).

  • A prospective cohort study evaluated rates of HCV and HIV acquisition in 428 injection drug users in England. At baseline, 44% were infected with HCV and 4% with HIV. After 1 year, the conversion rate for HCV was 42/100 person-years and for HIV was 3.4/100 person-years (5).

  • A cross-sectional study evaluated rates of blood-borne pathogens in 716 injection drug users. Among patients who had injected for 1 year or less, the prevalence of HCV was 65%, of HBV, 50%, and of HIV, 14%. In the multivariate analysis, HCV infection was independently associated with daily injection (vs. less than daily; OR, 4.40 [CI, 1.01 to 19.10]), injection of any cocaine in the last 6 months (OR, 5.25 [CI, 1.24 to 22.22]), and duration of drug use (OR, 2.14 [CI, 1.17 to 3.94] for more than 6 months compared to less than 6 months of use) (6).

  • Snorting cocaine intranasally seems to be a risk factor for HCV transmission, presumably through the sharing of straws (7); however, the strength of the association remains controversial.

Rationale
  • The use of illicit drugs by injection and some noninjection routes increases the risk of acquiring hepatitis C and other bloodborne pathogens.

  • Multimodality interventions reduce the risk for seroconversion more than single-method interventions.

Comments
  • Snorting cocaine intranasally seems to be a risk factor for HCV transmission, presumably through the sharing of straws.

  • Validated instruments to obtain this information would be helpful.

Ask all patients about high-risk sexual practices and advise preventive measures. 
  • Inquire about multiple sex partners, high-risk sexual practices, partners with a history of hepatitis C disease or risk factors, and history of sexually transmitted diseases.

  • Advise patients who engage in high-risk sexual practices to use condoms and other precautions to protect themselves and their partners.

  • Administer vaccines for hepatitis A and B in patients who engage in high-risk sexual practices if they are not already immune.

Evidence
  • A 2015 CDC guideline on sexually transmitted diseases covers general principles, special populations (including pregnancy, adolescents, and LGBT), and general discussion with recommended guidelines on treating each of the major STIs. The report includes a section on HCV as an emerging infection, including preventive measures (1).

  • A 2008 systematic review of behavioral counseling to prevent sexually transmitted infections in adolescents and adults included 15 randomized trials. Most trials found that adults receiving multiple intervention sessions had a small reduction in sexually transmitted infections (8).

  • A U.S. population-based study used NHANES data from 1999 to 2002 to determine HCV prevalence and risk factors. The prevalence of HCV was 1.6%, with the highest prevalence among adults aged 40 to 49 (4.3%). Risk factors included history of injection drug use, more than 20 lifetime sexual partners, and blood transfusion before 1992 (3).

  • A cross-sectional study evaluated rates of HCV in 154 spouses of patients with viremic HCV. Antibodies to HCV were found in 27% of spouses (9).

  • A case-control study evaluated risk factors for HAV infection among 67 men who have sex with men during a New York outbreak of HAV. In the multivariate analysis, independent risk factors for HAV included having oral-anal intercourse (OR, 17.5 [CI, 2 to 152]), as well as digital-rectal intercourse, group sex, and having more than one anonymous sexual partner (ORs not given) (10).

Rationale
  • Sexual transmission of hepatitis C occurs, but is generally accepted to be low and associated with specific risk factors and/or high-risk behaviors. Risks are shared with other pathogens including hepatitis A and B.

Ask all patients if they have or are considering getting tattoos or body piercings. 
  • Ask about the circumstances of any tattoos already acquired.

  • Advise patients about the potential risks if sterile equipment and appropriate cleaning are not used.

  • Discourage tattooing and body piercing unless single-use equipment and ink or appropriate sterilization can be guaranteed.

Evidence
  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended testing for hepatitis C at least once in a variety of high-risk groups including patients with unregulated tattoos (11).

  • A cross-sectional study evaluated risk factors for HCV among 1331 prisoners in Puerto Rico. The prevalence of HCV was 27% overall. Injection drug use was the strongest predictor of HCV infection (OR, 5.6 [CI, 3.2 to 9.7]). Among noninjection drug users, risk factors included unregulated tattooing (OR, 2.6 [CI, 1.3 to 5.5]) (12).

Rationale
  • The needles and ink used for tattooing and body piercing may transmit HCV, HBV, and HIV.

Comments
  • Strict adherence to one-time use of disposable equipment or sterilization of equipment between clients and single-use tattoo ink is essential to prevent viral hepatitis transmission. If these guidelines are adhered to, tattoos and ear piercings can be obtained safely without increasing the risk for viral hepatitis acquisition.

Routinely inquire about employment or volunteer work that may put the patient at risk for exposure to HCV infection.  
  • Advise patients who work or volunteer in health care, public safety (first responders), emergency medical services, or home health infusion therapy about the following:

    • The risks and prevention of blood-borne infection (needlestick accidents from infected patients may result in transmission of HCV)

    • The importance of barrier precautions (splash accidents that result in mucous membrane contamination have been suggested but not proven as a risk factor)

    • Infection-control practices, such as prohibition of the recapping of needles, should be employed

Evidence
  • A retrospective cohort study evaluated risk factors for HCV among 1677 hospital employees who underwent testing. The prevalence of HCV infection was 1.4%. In the multivariate analysis, hepatitis B core antigen positivity, a history of blood transfusion, and a needlestick injury were factors independently associated with HCV infection (13).

  • A retrospective study used data from prior cohort studies to determine risk factors for HCV among first responders. The overall prevalence ranged from 1.3% to 3.6%. HCV was not associated with skin exposure to blood (RR, 1.1 [CI, 0.3 to 4.2]), but was associated with nonoccupational exposures such as history of sexually transmitted diseases, use of illegal drugs, and blood transfusion before 1992 (14).

  • A prospective cohort study evaluated risk for HCV transmission in 646 health care workers after occupational exposure to blood or other high-risk fluids from HCV-infected patients. After hollow-bore needlestick injuries, the rate of transmission was 1.2%; there were no cases of HCV transmission after other types of exposure (15).

Rationale
  • Exposure to infected blood or other body fluids may carry a risk of transmitting hepatitis viruses.

  • Occupational exposure to blood and body fluids is a low-level but very real risk factor for hepatitis C and B transmission.

Comments
  • Although the overall risk for HCV infection may not exceed that in the general population, the risk may be increased when the prevalence of infection is high in the specific targeted population.

  • The risk for HCV infection appears to be increased with hollow-bore needle exposure.

Screen patients born between 1945 and 1965 and those with potential exposure to blood-borne infection. 
  • Screen all patients with any of the following risk factors at least once, and annually in the case of ongoing high-risk exposure:

    • Birth between 1945 and 1965

    • Illicit intravenous or intranasal drug use (past or present)

    • Chronic hemodialysis treatment (persons who have ever been on hemodialysis)

    • Persons who were ever incarcerated

    • Repeatedly elevated serum ALT levels

    • Receipt of blood or blood components (e.g., red cells, platelets, fresh-frozen plasma) or solid-organ transplantation before July 1992 or from a known HCV-positive donor, or receipt of clotting factor concentrates before 1990

    • Specific high-risk exposure to known HCV-positive blood (in health care workers), including needlestick injuries or other sharp exposure and mucosal exposure

    • HIV infection

    • Being the child of an HCV-positive woman

    • History of multiple sex partners, sexually transmitted diseases, or survival sex work

    • Birth in high-risk regions of the world

  • Consider screening for hepatitis C in long-term sex partners of HCV-positive individuals.

  • See module Screening for Hepatitis C.

  • See Comparative Guidelines: Screening for Hepatitis C Virus.

Evidence
  • A 2015 CDC guideline on sexually transmitted diseases covers general principles, special populations (including pregnancy, adolescents, and LGBT), and general discussion with recommended guidelines on treating each of the major STIs. The report includes a section on HCV as an emerging infection, including the recommendation for annual screening for BCV in patients coinfected with HIV (1).

  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended testing for hepatitis C at least once in patients born between 1945 and 1965 and screening of additional patients with risk factors for hepatitis C, including HIV infection, exposure to hemodialysis, receipt of unregulated tattoos, children of women with HCV, recipients of blood transfusions or organ transplants, and health care workers with exposures to HCV. The guideline recommended annual screening in patients with active injection drug use and in men with HIV infection who have unprotected sex with men (11). (Last accessed March 6, 2015.)

  • A 2014 WHO guideline on the screening and management of patients with hepatitis C recommended screening patients from a high-prevalence population and those with a history or potential exposure.

  • A 2013 guideline from the U.S. Preventive Services Task Force recommended screening for hepatitis C once in all persons born between 1945 and 1965, as well as targeted screening of people with risk factors (16).

  • A 2012 CDC guideline recommended that persons born from 1945 to 1965 should receive one-time testing for HCV without prior ascertainment of HCV risk (17).

  • A 2013 systematic review of the clinical outcomes of screening for hepatitis C found few studies, and none comparing screening to no screening. Screening strategies targeting persons with multiple risk factors found many cases of hepatitis C, with number-needed-to-screen of 20 (18).

  • A 2012 cost-effectiveness analysis compared primary care-based birth cohort screening of individuals born between 1945 and 1965 to screening based on risk factors. Birth cohort screening was cost effective, with incremental cost-effectiveness ratio of $35,700 per QALY if subsequent treatment was with direct-acting antivirals plus pegylated interferon and ribavirin, and $15,700 per QALY if subsequent treatment was with pegylated interferon plus ribavirin without direct-acting antiviral therapy (19).

  • A 2012 cost-screening effectiveness analysis compared screening the 1946 to 1970 birth cohort with risk-based screening for HCV. In the base analysis, birth cohort screening was cost-effective at $37,700 per QALY; the result was generally robust in sensitivity analysis (20).

  • A 2012 cost-effectiveness analysis evaluated general population screening and birth cohort (1945 to 1965) screening for HCV. Compared to targeted screening based on risk factors, both strategies were cost-effective when rates of HCV seropositivity were >0.53% (21).

Rationale
  • Adults born from 1945 to 1965 are at increased risk of HCV infection and screening this birth cohort has been shown to be cost-effective.

Screen by checking for antibody to HCV, using laboratory-based or point-of-care testing. 
  • Screen by checking for antibody to HCV:

    • In most office settings test for antibody to HCV (anti-HCV) in the serum

    • In community settings and some office settings consider using a point-of-care antibody test

    • Recognize that in some immunosuppressed individuals with suspected HCV infection or those with suspected acute infection, testing for anti-HCV by ELISA may be negative despite active infection. In this circumstance, test for HVC RNA

  • If antibody testing is positive perform quantitative HCV RNA testing.

  • Interpret the results in the following ways:

    • Positive ELISA with negative RNA indicates either false-positive ELISA or cleared infection (spontaneous clearance or successful treatment)

    • Positive ELISA with positive RNA indicates active chronic infection

    • Negative ELISA with positive RNA indicates acute infection or infection in immunosuppressed individuals

  • Do not use RIBA to test for HCV.

  • See module Screening for Hepatitis C.

  • See table Interpretation of Hepatitis C Virus Testing.

  • See Comparative Guidelines: Screening for Hepatitis C Virus.

Evidence
  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended performing an initial anti-HCV test, with a sensitive RNA test in patients who test positive for antibody (11). (Last accessed March 6, 2015.)

  • A 2013 CDC guideline on testing for HCV recommended testing for HCV beginning with a rapid or laboratory-based blood test for HCV antibody, followed by testing for HCV RNA among patients with HCV antibody (22).

  • A 2012 systematic review of the accuracy of point-of-care testing for HCV performed a meta-analysis of 18 studies. The studies compared the accuracy of a point-of-care test of blood, plasma, serum, or an oral sample to a variety of reference standards in a variety of risk groups. Overall, whole blood and finger stick tests had a sensitivity of 98.9% (CI, 94.5% to 99.8%) and specificity of 99.5% (CI, 97.5% to 99.9%); serum and plasma point-of-care tests had sensitivity of 98.9% (CI, 96.8% to 99.6%) and specificity of 99.7% (CI, 99.3 to 99.9%); oral fluid point-of-care tests had sensitivity of 97.1% (CI, 94.7% to 98.4%) and specificity of 98.2% (CI, 92.2% to 99.6%) (23).

  • A 2004 systematic review of screening for HCV assessed the accuracy of diagnostic tests. There were 10 studies of the accuracy of third-generation ELISA tests which found sensitivity ranging from 94% to 100% and specificity of 97% to 98.8% (24).

  • A 2001 systematic review assessed the diagnostic accuracy of third-generation tests for HCV and included 10 studies. Reference standards varied. Overall, the third-generation ELISA antibody test had sensitivity and specificity of 100% and 100% respectively in blood donors and patients on hemodialysis, and 97.2% and 100% respectively in patients with chronic liver disease, with sensitivity ranging from 98.6% to 99.9% in panel tests of sera. Third-generation RIBA had sensitivity and specificity respectively of 59.3% and 91.1% in blood donors, 100% and 100% respectively in patients with chronic liver disease, and 78.8% and 80% respectively in patients on hemodialysis (25).

Rationale
  • Most patients with positive ELISA for anti-HCV have been infected with HCV but only positive testing for HCV RNA indicates active infection.

  • The second- and third-generation ELISA tests are highly sensitive and specific. The RNA test confirms active infection and is the appropriate next step as it confirms infection and is needed to assess the individual for treatment.

  • Point-of-care tests are accurate and can facilitate community-based testing.

Comments
  • ELISA has lower sensitivity in immunosuppressed patients, including patients after transplant, those with HIV, and patients receiving hemodialysis (26; 27; 28).

Do not routinely screen patients who are at a lower risk of acquiring HCV infection. 
Evidence
  • Consensus.

Rationale
  • Screening is unlikely to be cost effective because of the high cost of testing and the generally slow natural history of infection, as well as the toxicities and high cost associated with treatment.

Comments
  • The development of inexpensive screening tests, methods to identify patients at risk for rapid progression, and availability of less toxic and less costly therapies may lead to a recommendation of universal screening.

Be aware that most patients with HCV are asymptomatic and should be diagnosed through screening. 
Evidence
  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended testing for hepatitis C at least once in patients born between 1945 and 1965 and screening of additional patients with risk factors for hepatitis C, including HIV infection, exposure to hemodialysis, receipt of unregulated tattoos, children of women with HCV, recipients of blood transfusions or organ transplants, and health care workers with exposures to HCV (11). (Last accessed March 6, 2015.)

  • A 2013 guideline from the U.S. Preventive Services Task Force recommended screening for hepatitis C once in all persons born between 1945 and 1965, as well as targeted screening of people with risk factors including injection drug use, blood transfusion before 1992, receipt of hemodialysis, incarceration, tattoos, and birth to a mother infected with HCV. The guideline noted that testing for HCV is part of the work-up for abnormal liver function tests (16).

  • A 2013 systematic review of the world-wide prevalence of HCV included 232 studies. The global prevalence was estimated at 2.8%, with high prevalence (>3.5%) in central and east Asia, and North Africa/Middle East, much of Latin America and Australasia, and low prevalence (<1.5%) in North American, Asia Pacific, and tropical Latin America (29).

  • A U.S. population-based study used NHANES data from 1999 to 2002 to determine HCV prevalence and risk factors. The prevalence of HCV was 1.6%, with the highest prevalence among adults aged 40 to 49 (4.3%). Risk factors included history of injection drug use, more than 20 lifetime sexual partners, and blood transfusion before 1992 (3).

  • The National Hepatitis Screening Survey, a cross-sectional screening study, evaluated the presence of HCV in 14,000 patients from 40 centers across the U.S. The prevalence of HCV was 7%, and 3% of patients had both HCV and hepatitis B infection. Risk factors for HCV included intravenous drug use, blood transfusions, hemodialysis, and having sex with and intravenous drug user (4).

Rationale
  • Individuals with a history of risk factors are more likely to test positive for HCV infection than those without this history.

Comments
  • A positive risk-factor history should prompt further evaluation for HCV as well as HBV and HIV infection.

Test for hepatitis C in patients with clinical symptoms or signs suggestive of liver disease. 
  • Consider the diagnosis of hepatitis C in patients with the following symptoms or signs:

    • Unexplained fatigue or malaise

    • Jaundice

    • Fluid retention

    • Thrombocytopenia

    • Anemia

    • GI bleeding

    • Hepatomegaly or splenomegaly

    • Signs of cirrhosis, such as ascites, spider angiomata, lower limb edema, or gynecomastia

    • Needle tracks on skin exam suggestive of intravenous drug use

    • Abnormal liver tests

  • See table Laboratory and Other Studies for Hepatitis C.

Evidence
  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended testing for hepatitis C in patients with unexplained chronic liver disease or hepatitis, including those with isolated elevated ALT (11). (Last accessed March 6, 2015.)

  • A 2013 guideline from the U.S. Preventive Services Task Force recommended screening for hepatitis C once in all persons born between 1945 and 1965, as well as targeted screening of people with risk factors including injection drug use, blood transfusion before 1992, receipt of hemodialysis, incarceration, tattoos, and birth to a mother infected with HCV. The guideline noted that testing for HCV is part of the work-up for abnormal liver function tests (16).

  • A cross-sectional study evaluated the prevalence of HCV in 6283 adults from a population-based sample in France. The prevalence of HCV was 1.15%. Among patients with HCV antibody, 81% had HCV RNA and 50% had an abnormal ALT (30).

  • A cross-sectional study described risk factors and lab values in 6917 patients with HCV enrolled in a clinical trial. Over 3 years of follow-up, 35% of patients had persistently normal ALT and GGT levels (31).

  • A population-based cross-sectional study determined the prevalence of HCV infection among 4820 asymptomatic adults and the proportion of infected adults with elevated liver enzymes. The prevalence of HCV was 2.4%; 54% of infected patients had an elevated AST and 46% had a normal ALT (32).

  • A 2005 narrative review on the natural history of HCV infection estimated that the rate of development of cirrhosis over 10 to 20 years of HCV infection is between 5% and 25% (33).

Rationale
  • Individuals with chronic liver disease have a high likelihood of having HCV especially after other causes have been excluded.

Recognize disease processes that may complicate hepatitis C infection.  
  • Recognize the following disease states as potential complications of chronic HCV infection:

    • Cirrhosis

    • Hepatocellular carcinoma

    • Cryoglobulinemia

    • Membranoproliferative glomerulonephritis

    • Porphyria cutanea tarda

    • Autoimmune thyroiditis, although it occurs mainly with interferon therapy

  • Consider the following disorders as being possibly but not definitely associated with chronic HCV infection:

    • Sjögren's syndrome

    • Lichen planus

    • Seronegative arthritis

    • Aplastic anemia

    • B-cell non-Hodgkin's lymphoma

    • Mooren's corneal ulcer

    • Diabetes mellitus

  • See figure Hepatitis C-associated Cryoglobulinemia.

  • See figure Lichen Planus Involving Buccal Mucosa.

  • See figure Hepatitis C-Associated Porphyria Cutanea Tarda.

Evidence
  • A 2011 systematic review of the risk of autoimmune thyroiditis with interferon therapy in patients with HCV compared to controls with HBV included five studies with 1081 participants. Patients with HCV treated with interferon were more likely to be diagnosed with autoimmune thyroiditis (pooled OR, 4.98 [CI, 1.6 to 15.9]) (34).

  • A prospective study described findings and clinical course in 231 patients with mixed cryoglobulinemia. Overall, 92% of patients had hepatitis C and 42% had antibodies to hepatitis B. Eighty-one percent presented with purpura, 80% with weakness, 72% with arthralgia, 58% with peripheral neuropathy, 36% with Raynaud phenomenon, and 29% with sicca syndrome (35).

  • A prospective study evaluated the rates of cryoglobulinemia in 432 consecutive patients with chronic liver disease, among whom 303 had HCV. Among patients with HCV, cryoglobulinemia was initially found in 46%; risk factors included cirrhosis and longer duration of liver disease. Approximately half of patients with cryoglobulinemia had clinical manifestations and the incidence of new cryoglobulinemia was 6% per year (36).

  • A case-control study evaluated 175 consecutive patients with non-Hodgkin's lymphoma and 350 controls to determine the association between HCV and lymphoma. The prevalence of HCV was higher in patients with lymphoma than in controls (37% vs. 9%, P=0.0001). Mixed cryoglobulinemia was found in 22% of patients with HCV, but only 21% of those with cryoglobulinemia were symptomatic (37).

  • A cross-sectional study evaluated risk factors for diabetes mellitus in 1117 patients with chronic viral hepatitis. In the multivariate analysis, HCV (OR, 2.1 [CI, 1.12 to 3.90]) and age were independently associated with the development of diabetes (38).

  • A 2004 narrative review of HCV and HBV in liver transplantation noted that HCV is the underlying disease in 50% of liver transplants in North American and Europe (39).

  • A 2008 narrative review discussed HCV-related renal disease, noting that membranoproliferative glomerulonephritis associated with cryoglobulinemia is the most common (40).

  • A 2009 narrative review discussed cryoglobulinemia associated with HCV (41).

Rationale
  • Cirrhosis from HCV is a well-documented complication that may lead to end-stage liver disease or hepatocellular carcinoma.

  • Cryoglobulinemia and glomerulonephritis are complications of persistent HCV infection rather than of liver disease.

Comments
  • Although studies have reported that as many as 50% of patients with chronic hepatitis C have circulating cryoglobulins, the clinical syndrome of cryoglobulinemia is seen in less than 5% of patients.

  • The mechanism that links HCV to porphyria cutanea tarda is poorly understood.

  • The presence of leukocytoclastic vasculitis in the setting of cryoglobulinemia is highly suggestive of HCV infection.

Use sequential testing, first for anti-HCV and then for HCV RNA, to establish the diagnosis of hepatitis C. 
  • Use the following criteria for diagnosis of hepatitis C:

    • Positive ELISA for anti-HCV and

    • Positive HCV RNA

  • Patients suspected of having acute or chronic HCV infection should first be tested for anti-HCV.

    • If anti-HCV is positive, test for HCV RNA

    • Perform HCV RNA test if HCV infection is suspected but anti-HCV test is negative in patients who are immunocompromised (e.g., patients with chronic renal failure, HIV patients, and organ transplant recipients) or who are suspected of having acute HCV infection

  • See table Laboratory and Other Studies for Hepatitis C.

  • See table Interpretation of Hepatitis C Virus Testing.

Evidence
  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended performing an initial anti-HCV test, with a sensitive RNA test in patients who test positive for antibody (11). (Last accessed March 6, 2015.)

  • A 2014 WHO guideline on the screening and management of patients with hepatitis C recommended that patients with a positive HCV antibody undergo testing for HCV RNA.

  • A 2013 CDC guideline on testing for HCV recommended testing for HCV beginning with a rapid or laboratory-based blood test for HCV antibody, followed by testing for HCV RNA among patients with HCV antibody (22).

  • A 2012 systematic review of the accuracy of point-of-care testing for HCV included 18 studies. The studies compared the accuracy of a point-of-care test of blood, plasma, serum, or an oral sample to a variety of reference standards in a variety of risk groups. Overall, whole blood and fingerstick tests had a sensitivity of 98.9% (CI, 94.5% to 99.8%), and specificity of 99.5% (CI, 97.5% to 99.9%); serum and plasma point-of-care tests had sensitivity of 98.9% (CI, 96.8% to 99.6%) and specificity of 99.7% (CI, 99.3% to 99.9%); oral fluid point-of-care tests had sensitivity of 97.1% (CI, 94.7% to 98.4%) and specificity of 98.2% (CI, 92.2% to 99.6%) (23).

  • A 2007 systematic review of the accuracy of molecular diagnostic tests for the diagnosis and follow-up of HCV included qualitative and quantitative tests. Overall, qualitative PCR tests are highly accurate; the review noted that they are generally used to follow treatment response (42).

  • A 2004 systematic review of screening for HCV assessed the accuracy of diagnostic tests. There were 10 studies of the accuracy of third-generation ELISA tests which found sensitivity ranging from 94% to 100% and specificity of 97% to 98.8% (24).

  • A 2001 systematic review that assessed the diagnostic accuracy of third-generation tests for HCV included 10 studies. Reference standards varied. Overall, the third-generation ELISA antibody test had sensitivity and specificity of 100% and 100% respectively in blood donors and patients on hemodialysis, and 97.2% and 100% respectively in patients with chronic liver disease, with sensitivity ranging from 98.6% to 99.9% in panel tests of sera. Third-generation RIBA had sensitivity and specificity of 59.3% and 91.1% respectively in blood donors, 100% and 100% respectively in patients with chronic liver disease, and 78.8% and 80% respectively in patients on hemodialysis (25).

  • A cross-sectional study evaluated the prevalence of HCV in 6283 adults from a population-based sample in France. The prevalence of HCV was 1.15%. Among patients with HCV antibody, 81% had HCV RNA and 50% had an abnormal ALT (30).

  • A cross-sectional study described risk factors and lab values in 6917 patients with HCV enrolled in a clinical trial. Over 3 years of follow-up, 35% of patients had persistently normal ALT and GGT levels (31).

  • A population-based cross-sectional study determined the prevalence of HCV infection among 4820 asymptomatic adults and the proportion of infected adults with elevated liver enzymes. The prevalence of HCV was 2.4%; 54% of infected patients had an elevated AST and 46% had a normal ALT (32).

  • A cross-sectional study tested for anti-HCV antibody and HCV RNA in 131 HIV-infected patients and 102 HIV-negative controls. HCV RNA was detected in 31 HIV-positive patients (24%) and in 2 (1.9%) HIV-negative controls. Among patients without HCV antibody, 20% of HIV-infected patients tested positive for HCV RNA, compared with 0% of controls (28).

Rationale
  • In individuals with positive ELISA for anti-HCV, testing for HCV RNA is necessary to demonstrate active vs. resolved infection or false-positive ELISA.

  • ALT levels are variable but normal levels do not rule out the diagnosis.

  • Testing for HCV RNA is especially useful when anti-HCV cannot be detected (e.g., in immunosuppressed patients, patients with chronic renal failure, HIV patients, and recent recipients of organ transplants).

Comments
  • Approximately 20% of patients with HCV infection will successfully clear the virus; they will have anti-HCV antibody but no HCV RNA, Such patients are not at risk for complications of HCV.

  • Anti-HCV antibody testing may be less sensitive in immunosuppressed patients such as those with renal failure or organ transplantation.

  • The diagnosis of active HCV infection is based on the presence of circulating HCV RNA, regardless of ALT level or whether anti-HCV antibodies are present.

Perform HCV genotyping at the time of HCV diagnosis. 
Evidence
  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended performing genotyping in patients with positive HCV RNA, in order to select the most appropriate therapy. Rarely, genotyping assays may indicate the presence of a mixed infection (e.g., genotypes 1a and 2). When treatment is necessary, the choice of antiviral combination and duration of treatment should maximize efficacy against each genotype represented in the assay. When the correct combination or duration is unclear, expert consultation should be sought (11). (Last accessed March 6, 2015.)

  • A cross-sectional study described the epidemiology of HCV infection among 8558 U.S. veterans. The prevalence of HCV infection was 35%. Among a subset of 215 HCV-positive participants, 96% have viremia; genotypes included 1a (50.5%), 1b (22.8%), 2a (1.9%), 2b (9.7%), and 3a (12.1%) (43).

  • A 2000 narrative review discussed the significance of HCV genotypes, noting that HCV can be classified into at least six major genotypes based on difference in genomic sequence. HCV genotypes are determined by restriction fragment length polymorphism, by direct sequence analysis, or by reverse hybridization to genotype-specific oligonucleotide probes and may be further classified into subtypes, such as genotype 1a, 1b, etc. Genotype 1 is the most common genotype (70% to 75%) in the U.S., followed by genotypes 2 and 3 (25% to 30%) (44).

Rationale
  • Genotype determines the optimal treatment.

Comments
  • HCV genotyping should be performed before treatment to plan for medication selection, dosing, and duration of therapy, and to predict the likelihood of treatment response.

  • Once the HCV genotype has been identified, there is no need to repeat the test.

  • Different genotypes are more common in some areas of the world than in others.

Do not perform a liver biopsy to diagnose HCV or determine the degree of fibrosis; consider biopsy in specific circumstances to rule out other causes of liver disease.  
  • Perform a combination of indirect serum biomarkers (routine tests), direct serum biomarkers (components of the extracellular matrix produced by activated hepatic stellate cells), and vibration-controlled transient liver elastography to determine the degree of liver fibrosis in HCV patients.

  • Do not perform liver biopsy to diagnose HCV or to determine the degree of liver fibrosis in chronic hepatitis C unless unable to assess degree of fibrosis using other methods..

  • See table Laboratory and Other Studies for Hepatitis C.

  • See figure Hepatitis C Histology.

Evidence
  • The 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended combining direct biomarkers and vibration-controlled transient liver elastography as the most efficient approach to fibrotic assessment. A biopsy should be considered for any patient who has discordant results between the 2 modalities that would affect clinical decision making (11). (Last accessed March 6, 2015.)

  • An estimated 10% to 40% of patients with chronic HCV infection have normal ALT levels. A review of multiple studies found that 24% of patients had normal liver histology, 54% had mild chronic hepatitis, and 21% had moderate chronic hepatitis (45).

  • After biopsy, approximately 1% of patients require hospitalization for pain management, 1 in 1000 require a blood transfusion, and 1 in 10,000 may exsanguinate (46; 47).

  • Liver biopsy is the most expensive component of the evaluation. Cost estimates vary between $750 and $2000 (48).

Rationale
  • Liver biopsy has prognostic value but is not essential before initiating treatment.

  • Liver biopsy is costly, carries some risk, and may discourage patients from proceeding with treatment.

Comments
  • Only trained and experienced clinicians should undertake liver biopsy, which is a same-day, outpatient procedure that is performed with or without ultrasound guidance. Although classically performed by a gastroenterologist and/or hepatologist, many are now performed by interventional radiologists. Assessing liver histology also requires specialized expertise.

Consider other hepatic disorders in addition to HCV in the evaluation of patients with chronic hepatitis.  
  • Evaluate all patients with risk factors for HCV infection.

  • Evaluate all patients with HCV infection for HBV and HIV infection with the following tests:

    • HBsAg

    • Anti-HBs

    • HIV “fourth generation” combo assay

  • In the absence of viral hepatitis, consider the following potential causes of chronic hepatitis and in patients with HCV with appropriate risk factors:

    • Autoimmune hepatitis

    • Alcoholic hepatitis

    • NAFL/NAFLD/NASH

    • Drug-induced liver injury

    • Hemochromatosis

    • Wilson's disease

    • α1-antitrypsin deficiency

    • Celiac disease

  • Consider the following tests as appropriate in evaluating patients who may have these other disorders:

    • ANA

    • ASMA

    • Ferritin level

    • Transferrin saturation

    • Ceruloplasmin level

    • α1-antitrypsin level

    • Celiac panel

  • See table Differential Diagnosis of Hepatitis C.

Evidence
  • Mainly consensus.

Rationale
  • Chronic hepatitis may be a result of HCV or HBV infection, HCV/HBV coinfection, nonviral causes of chronic hepatitis, or HCV or HBV infection with coexisting nonviral causes of hepatitis.

  • HIV and HCV have similar risk factors. HIV/HCV coinfection also requires treatment for HIV.

  • In patients with other hepatic disorders, the presence of HCV may affect the prognosis and therapeutic plan.

Comments
  • Testing for HCV and HBV infection and for the causes of nonviral hepatitis is appropriate during the evaluation of patients with chronic hepatitis.

Consult a hepatologist when additional causes of hepatitis other than chronic HCV may be present. 
  • Consult a hepatologist to do the following:

    • Distinguish between chronic hepatitis C with coexistent autoimmune hepatitis, and chronic hepatitis C with autoimmune markers

    • Distinguish between chronic hepatitis C with coexistent hemochromatosis, and chronic hepatitis C with features of excessive hepatic iron accumulation

    • Distinguish between chronic hepatitis C with coexistent alcoholic liver disease, and chronic hepatitis C alone

    • Distinguish between chronic hepatitis C with coexistent NASH, and chronic hepatitis C alone

    • Perform a liver biopsy to clarify the diagnosis

Evidence
  • Consensus.

Rationale
  • Failure to recognize additional causes of liver injury may result in the failure to treat coexisting disease and an inaccurate assessment of response to treatment of chronic hepatitis C.

Comments
  • Expert consultation to identify key coexisting disorders and to develop a therapeutic plan that encompasses these disorders is reasonable.

  • Chronic hepatitis C genotype 3 infection is associated with steatosis.

Consider consultation and referral for management of hepatitis C, including referral to a clinical trials center for patients for whom standard-of-care therapy has failed. 
  • Consider consultation, particularly for the following patient groups:

    • Patients with HCV-associated cirrhosis with decompensation (ascites, hepatic encephalopathy, variceal bleeding) or hepatocellular carcinoma

    • Patients with extrahepatic manifestations of HCV infection, such as vasculitis

    • Patients with HBV/HCV or HIV/HCV coinfection

    • Patients who have relapsed or have not responded to initial treatment

Evidence
  • A prospective cohort study described outcomes in 407 patients with chronic HCV who were treated at the University of New Mexico, either by trained primary care clinicians at 21 rural sites or by specialists at an HCV clinic. Rates of SVR were similar in patients treated in primary care (58.2%) and those treated at the HCV clinic (57.5%, P=0.89). Rates of serious adverse events were higher in patients treated in the HCV clinic (13.7% vs. 6.9%, P= 0.02), which may be attributable to differences in the patient populations (49).

Rationale
  • Gastroenterologists, hepatologists, and infectious disease specialists are most likely to be familiar with the complex treatment regimens for hepatitis C and have the support staff in place to provide such therapy.

  • Gastroenterologists and hepatologists can perform liver biopsies to aid in the management of patients and have familiarity with appropriate management of decompensated cirrhosis and hepatocellular carcinoma, including transplant referral.

  • In underserved areas, primary care providers provided with an adequate support network can safely implement interferon-based therapy.

Comments
  • Whether the added level of complexity of triple therapy allows primary care physicians to also implement effective therapy models remains to be seen.

Consider referral to a transplant center for patients with decompensated cirrhosis (variceal bleeding, ascites, encephalopathy). 
  • Refer patients to a transplant center if they have:

    • Cirrhosis and a MELD score ≥10

    • GI bleeding caused by portal hypertension

    • Refractory ascites or an episode of spontaneous bacterial peritonitis

    • Recurrent hepatic encephalopathy or hepatocellular carcinoma.

Evidence
  • The 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended that patients with HCV and decompensated cirrhosis (moderate or severe hepatic impairment; Child-Turcotte-Pugh class B or C) be referred to a medical practitioner with expertise in that condition, ideally in a liver transplant center (11). (Last accessed March 6, 2015.)

  • A 2005 AASLD guideline on the evaluation of patients for liver transplantation recommended that patients with cirrhosis be referred for liver transplantation when they have evidence of hepatic dysfunction (MELD score ≥10) or have their first major complication (ascites, variceal bleeding, or hepatic encephalopathy (50).

  • A 2006 systematic review of the prognostic value of the MELD score compared with the Child-Pugh score for predicting mortality in patients with cirrhosis included 11 studies of patients on the waiting list for transplantation. Four studies showed that MELD was superior to Child-Pugh and 7 showed that it had similar predictive accuracy (51).

Rationale
  • Patients with MELD score ≥15, history of GI bleeding caused by portal hypertension, or spontaneous bacterial peritonitis have a predicted 1-year survival rate of 90% or lower.

  • Liver transplantation provides excellent survival outcomes for hepatocellular carcinoma in selected patients.

Hospitalize patients with bleeding, infection, or metabolic complications. 
  • Hospitalize patients with the following life-threatening complications of cirrhosis:

    • Esophagogastric variceal hemorrhage or other serious bleeding

    • Spontaneous bacterial peritonitis

    • Hepatorenal syndrome

    • Severe hepatic encephalopathy

    • Intractable ascites

Evidence
  • Consensus.

Rationale
  • Patients with life-threatening complications usually require intensive care (e.g., blood and albumin transfusion, intravenous antibiotics, intubation).

Comments
  • Hospitalization usually reflects the presence of features of end-stage liver disease and suggests the need for referral for transplantation evaluation.

Advise patients with chronic hepatitis C to avoid alcohol and to eat a balanced diet.  
  • Recommend abstinence from alcohol.

  • Recommend a balanced, nutritionally adequate diet.

  • Reserve dietary sodium restriction only for patients with decompensated cirrhosis and volume overload.

  • Note that there is no evidence on which to base a recommendation for treatment with herbal therapies, such as milk thistle or antioxidants.

  • Recommend avoidance of supplements unless studied and known to be safe for use in liver disease.

Evidence
  • A 2014 WHO guideline on the screening and management of patients with hepatitis C recommended asking all patients with newly diagnosed HCV about alcohol use and intervening to reduce drinking, and counseling patients with HCV to abstain from alcohol.

  • A retrospective cohort study evaluated the impact of alcohol consumption on clinical status in 120 Japanese patients with chronic liver disease from HCV and/or alcohol. Alcohol consumption did not correlate with serum ALT or HCV RNA levels or with inflammation on histology. However, rates of cirrhosis were lower among patients with HCV who did not drink alcohol (16.9%) than among those who were moderate (47.5%) or heavy (27.2%) drinkers (P<0.1) (52).

Rationale
  • Alcohol consumption seems to play a key role in accelerating the progression from chronic hepatitis C to cirrhosis and may interfere with the response to treatment.

  • No conclusive evidence has demonstrated a benefit from herbal therapy.

Comments
  • Whether alcohol enhances the replication of HCV or has an indirect effect on promoting viral injury remains uncertain.

Discuss antiviral therapy with all patients in whom HCV RNA is detected in serum. 
  • Encourage patients with chronic hepatitis C to consider antiviral treatment regardless of signs of progression of liver fibrosis.

  • Note that

    • Treating early can optimally preserve liver function and avoid complications.

    • Methods to determine degree of fibrosis can underestimate the actual condition of the liver.

  • Order the following lab tests in anticipation of treatment

    • CBC

    • INR

    • Hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase levels)

    • TSH if IFN will be used

    • Calculated GFR

  • Consider treatment in all HCV patients, and

    • That immediate treatment is the highest priority for those patients with advanced fibrosis (Metavir F3), those with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis.

    • That treatment is given a high priority for patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications.

    • That treatment might not be appropriate for patients with limited life expectancy (less than 12 months) due to non-liver-related comorbid conditions (HIV/HVC coinfection, cirrhosis, liver transplantation, and renal impairment).

    • Note that cirrhosis is not a contraindication to treatment; however, response rates may be lower than in the absence of cirrhosis.

    • That ongoing depression or severe mental illness may need additional support and assistance to adhere to treatment.

    • That patients with decompensated liver disease (e.g., variceal bleeding, ascites, encephalopathy, features of end-stage liver disease) may be treated with antiviral therapy but must first be referred for liver-transplant evaluation.

  • See table Drug Treatment for Hepatitis C.

  • See table Examples of HVC Drug Regimens.

Evidence
  • The 2015 AASLD/IDSA guideline section on when and in whom to initiate HCV therapy emphasized benefits of early treatment in patients without advanced fibrosis (Metavir F0 or F1), based on reviews of two RCTs (11). (Last accessed July 1, 2015.)

  • The 2014 AASLD/IDSA guideline recommended that immediate treatment be the highest priority for those patients with advanced fibrosis (Metavir F3), those with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C. Based on available resources, immediate treatment should be prioritized as necessary so that patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications are gien high priority. Evidence clearly supports treatment in all HCV-infected persons, except those with limited life expectancy (less than 12 months) due to non-liver-related comorbid conditions (HIV/HVC coinfection, cirrhosis, liver transplantation, and renal impairment (11). (Last accessed March 6, 2015.)

  • A 2014 WHO guideline on the screening and management of patients with hepatitis C recommended that all patients with HCV be assessed for antiviral therapy.

  • A 2013 meta-analysis found that SVR after treatment of hepatitis C infection was associated with a reduced risk of hepatocellular carcinoma at any stage of fibrosis (53).

  • A 2000 narrative review on HCV discussed the natural history of the disease and noted that a substantial proportion of patients do not develop cirrhosis even after decades of infection (54).

Rationale
  • All patients with chronic hepatitis C are at risk for disease progression, although many patients do not progress.

Comments
  • The 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C stated that the goal of treatment of HCV-infected persons is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by an SVR (11). (Last accessed March 6, 2015)

  • If treatment is not pursued, patients should have routine follow-up monitoring of liver function for signs of disease progression.

Treat patients based on their genotype, degree of fibrosis, and previous treatment history with an approved regimen. 
Evidence
  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C stated that “successful hepatitis C treatment results in sustained virologic response (SVR), which is tantamount to virologic cure, and as such, is expected to benefit nearly all chronically infected persons. Evidence clearly supports treatment in all HCV-infected persons, except those with limited life expectancy (less than 12 months) due to non–liver-related comorbid conditions (HIV/HCV coinfection, cirrhosis, liver transplantation, and renal impairment). Urgent initiation of treatment is recommended for some patients, such as those with advanced fibrosis or compensated cirrhosis” (11). (Last accessed March 6, 2015.)

  • A systematic review of 1952 pivotal trials on combination ledipasvir plus sofosbuvir therapy in patients with chronic HCV found evidence of a greater than 94% SVR after 12 weeks of treatment in patients with genotype 1, among both treatment-naïve and treatment-experienced patients (55).

  • A 2014 HTA report on direct-acting antiviral agents discussed treatment with sofosbuvir and simprevir.

  • A phase-3 randomized, controlled trial compared treatment efficacy and safety of once daily ABT-450 (paritaprevir) 150 mg; ritonavir, 100 mg; and ombitasvir, 25 mg; plus twice-daily dasabuvir, 250 mg, with or without ribavirin (dosed by body weight) in 724 patients with genotype 1a or 1b hepatitis C. At 12 weeks, genotype 1b patients experienced a high rate of SVR to therapy with or without ribavirin, but failure rate among genotype 1a patients was higher without the addition of ribavirin (genotype 1b: 99.5% with ribavirin and 99.0% without ribavirin; genotype 1a: 97.0% with RBV and 90.2% without ribavirin). A decrease in level of hemoglobin was significantly more common in patients receiving ribavirin (56).

  • A phase-3, open-label trial found noninferiority for 8 weeks vs. traditional 12 weeks regimen of ledipasvir plus sofosbuvir in 647 previously untreated patients with HCV genotype 1 infection without cirrhosis, with or without the addition of ribavirin. There was no statistical significant difference in SVR among the three groups (8 weeks of ledipasvir–sofosbuvir, 94% [CI, 90 to 97]; 8 weeks of ledipasvir–sofosbuvir plus ribavirin, 93% [CI, 89 to 96]; 12 weeks of ledipasvir–sofosbuvir, 95% [CI, 92 to 98]) (57).

  • A paper reported results of two phase 3 trials, one an observational study of 12 weeks of sofosbuvir, pegylated interferon, and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6; and a second randomized noninferiority trial comparing sofosbuvir and ribavirin for 12 weeks to pegylated interferon plus ribavirin for 24 weeks in 499 patients with HCV genotypes 2 or 3. In the observational study, 90% of patients had SVR 12 weeks after therapy. In the randomized trial, the overall rate of SVR were the same in both groups (67% and 67%), and the sofosbuvir group had fewer adverse events (58).

  • A randomized trial compared daclatasvir plus sofosbuvir to the same regimen plus ribavirin for 24 weeks in 88 untreated patients with HCV genotypes 1, 2, or 3, and separately randomized 123 patients with either untreated HCV genotype 1 to daclatasvir plus sofosbuvir or the same regimen plus ribavirin for 12 (in 82 previously untreated patients) or 24 weeks (in 41 patients with treatment failure with telaprevir or boseprevir). Overall, SVR was seen in 98% of previously untreated patients with genotype 1, 98% of patients with genotype 1 and previous treatment failure, 92% of patients with genotype 2, and 89% of patients with genotype 3. Adverse events included fatigue, headache, and nausea (59).

  • The results of two randomized trials were reported. The first trial compared sofosbuvir plus ribavirin for 12 weeks in 278 patients with HCV genotypes 2 or 3 who were not candidates for interferon, and the second compared 12 weeks of sofosbuvir plus ribavirin to 16 weeks of the therapy in 201 patients with HCV genotypes 2 or 3 who had not responded to interferon. In the first study, the rate of SVR was higher in the sofosbuvir group (78% vs. 0%, P<0.001). In the second study, the rate of SVR was higher in the 16-week group (73% vs. 50%, P<0.001) (60).

Rationale
  • Combination therapy enhances response rates.

Comments
  • On March 14, 2015, the FDA issued a drug safety communication regarding serious symptomatic bradycardia in patients taking amiodarone together with sofosbuvir and another direct-acting antiviral agent (such as in combination with ledipasvir or with simeprevir)

  • SVR usually is accompanied by a return to normal serum ALT level and an improvement in or resolution of hepatic lesions (61; 62).

  • SVR is maintained on follow-up in approximately 95% of patients (61; 62).

  • For patients with mild to moderate renal impairment (CrCl >30 mL/min), the AASLD/IDSA guidelines on testing, managing, and treating hepatitis C do not recommend dosage adjustments when using sofosbuvir, simeprevir, fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg), or fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg).For patients with CrCl below 30 mL/min, no safety and efficacy data are available for these patients. Consultation with an expert is recommended (11). (Last accessed March 6, 2015.)

  • Contraindications to interferon therapy include anemia, cardiovascular disease, renal insufficiency, severe chronic lung disease, and uncontrolled diabetes.

  • The complexity of therapy and nuances of the management of myriad side effects require vigilant and experienced providers along with nursing and pharmacy support.

Test for immunity to HAV and HBV infection, and then begin to vaccinate susceptible patients before initiating HCV treatment.  
  • Measure presence of anti-HAV (total); if negative, give HAV vaccine.

  • Measure presence of anti-HBc and anti-HBs; if negative, give HBV vaccine.

Evidence
  • A prospective study evaluated the effect of HAV acquisition in 432 patients with chronic HCV and 163 patients with chronic HBV. After 7 years, 17 patients with HCV and 10 with HBV acquired HAV. Among patients with chronic HCV, 7 (41%) developed fulminant hepatic failure, among whom 6 died (63).

Rationale
  • Superinfection by HAV and HBV may be devastating in patients with underlying chronic hepatitis C.

Comments
  • Testing for HAV and HBV and subsequent vaccination is the standard of care.

Treat special populations.  
  • Prioritize treating patients coinfected with HIV.

  • Be alert to potential drug-drug interactions in patients undergoing simultaneous HIV and HCV treatment regimens.

  • Prioritize treating patients with decompensated cirrhosis.

  • Prioritize treating women before they are pregnant.

  • Avoid treating women during pregnancy if possible.

  • See table Drug Treatment for Hepatitis C.

  • See table Examples of HCV Drug Regimens.

Evidence
  • A 2015 AASLAD/IDSA guideline on patients with HIV/HCV coinfection updated various drug-drug interactions between HIV and HCV regimens, and advised that treatment of HIV/HCV-coinfected patients requires continued awareness and attention to the complex drug interactions that can occur between direct-acting antiviral agents and antiretroviral medications (11).

  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended prioritizing the treatment of several groups of patients:

    • Patients coinfected with HIV, since they have an increased risk of liver fibrosis and a more rapid progression to death following decompensation, combined with a lack of widespread access to liver transplantation and poor outcomes following transplantation, argue for treatment prioritization in this population, regardless of the current fibrosis stage.

    • Women before they become pregnant, as mother-to-child transmission of HCV does not occur if the woman is not viremic. However, the safety and efficacy of treating women who are already pregnant to prevent transmission to the fetus have not yet been established, and thus treatment is not recommended for pregnant women (11).

Rationale
  • Optimal chance for SVR depends on recognizing and individualizing care to special populations of HCV patients.

Comments
  • SVR usually is accompanied by a return to normal serum ALT level and an improvement in or resolution of hepatic lesions (61; 62).

  • SVR is maintained on follow-up in approximately 95% of patients (61; 62).

  • The complexity of therapy and nuances of the management of myriad side effects require vigilant and experienced providers along with nursing and pharmacy support.

Re-treat patients who do not respond to therapy based in their genotype and initial regimen. 
Evidence
  • A 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended treatment regimens for patients for whom initial therapy with ribavirin and pegylated interferon failed (11). (Last accessed March 6, 2015.)

  • A systematic review of 1952 pivotal trials on combination ledipasvir plus sofosbuvir therapy in patients with chronic HCV found evidence of a greater than 94% SVR after 12 weeks of treatment in patients with genotype 1, among both treatment-naïve and treatment-experienced patients (55).

  • A phase three open trial involving 440 treatment-experienced genotype 1 patients (79% 1a, 20% with cirrhosis) who failed initial interferon-RBV with or without a protease inhibitor, achieved 94% to 99% SVR after once daily combined ledipasvir and sofosbuvir, with or without ribavirin, depending on length of treatment (12 to 24 weeks, respectively) (64).

  • A randomized trial compared daclatasvir plus sofosbuvir to the same regimen plus ribavirin for 24 weeks in 88 untreated patients with HCV genotypes 1, 2, or 3, and separately randomized 123 patients with either untreated HCV genotype 1 to daclatasvir plus sofosbuvir or the same regimen plus ribavirin for 12 (in 82 previously untreated patients) or 24 weeks (in 41 patients with treatment failure with telaprevir or boseprevir). Overall, SVR was seen in 98% of previously untreated patients with genotype 1, 98% of patients with genotype 1 and previous treatment failure, 92% of patients with genotype 2, and 89% of patients with genotype 3. Adverse events included fatigue, headache, and nausea (59).

  • A randomized phase IIb trial compared simeprevir, 100 mg or 150 mg, to placebo (in addition to pegylated interferon plus ribavirin) in patients with HCV genotype I who had incomplete response to pegylated interferon plus ribavirin or who had a relapse after therapy. There were 396 patients in the simeprevir group and 66 in the placebo group. Overall, rates of SVR at 24 weeks were higher in the simeprevir groups (61% or 80% vs. 23%, P<0.001); rates of adverse events did not differ among the groups (65).

Rationale
  • Combination therapy or longer regimens in experienced patients often results in improved SVR.

For patients who experience mild side effects from pegylated interferon or ribavirin, consider dose reduction. 
  • Reduce drug doses in patients with granulocyte counts <750 cells/mL and discontinue drugs in patients with counts <500 cells/mL.

  • Reduce drug doses in patients with severe thrombocytopenia.

  • Reduce ribavirin dose in patients whose hemoglobin drops below 10 mg/dL. Consider the addition of erythropoietin, although data supporting enhanced SVR with erythropoietin supplementation are lacking.

  • Discontinue all drugs and seek appropriate care in the event of severe depression or suicidal ideation.

  • Be vigilant for side effects in patients on any interferon-based regimen.

  • See table Drug Treatment for Hepatitis C.

  • See table Examples of HCV Drug Regimens.

Evidence
  • In a U.S. multicenter randomized trial, which compared interferon monotherapy with interferon plus ribavirin, drug discontinuation was necessary in 14% of patients who were treated with interferon monotherapy and 21% of patients given combination therapy over 48 weeks. Eight percent of patients on combination therapy decreased the dose due to anemia (66).

Rationale
  • Drug reduction or discontinuation is necessary for some adverse events.

Comments
  • Short-term (<2 weeks) discontinuation of combination therapy does not reduce the SVR rate. Reduction of ribavirin dosing early (in the first 12 weeks) in combination pegylated interferon-α and ribavirin therapy may reduce SVR, but this appears to be less problematic in triple therapy.

Emphasize the usual slow progression of chronic hepatitis C in the absence of ongoing alcohol use, co-morbid HIV or HBV infection, co-morbid fatty liver disease, and other risks for progression.  
  • Discuss with and counsel patients about the typically slow progression of liver disease in chronic hepatitis C in the absence of ongoing alcohol use, concomitant infection with HIV or hepatitis B, or other insults to the liver (e.g., drug-induced liver injury).

  • Inform the patient that cirrhosis and liver cancer are not inevitable results of hepatitis C infection and in fact only ensue in a minority of infected patients.

  • Educate patients that the goal of treatment of HCV-infected persons is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by an SVR.

Evidence
  • The 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C stated that the goal of treatment of HCV-infected persons is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by an SVR (11). (Last accessed March 6, 2015.)

  • A retrospective cohort study reported long-term outcomes in military recruits who had blood drawn between 1948 and 1954. Among 8568 recruits, 17 (0.2%) were found to have HCV. After a follow-up time of 45 years, 11.8% developed clinical liver disease. Mortality was not increased in patients with HCV (adjusted RR, 1.48 [CI, 0.8 to 2.6]) (67).

  • A prospective cohort study described long-term outcomes in 1667 injection drug users with HCV. After a median follow-up time of 8.8 years, 40 patients developed end-stage liver disease (incidence of 3.1/1000 person-years). In the multivariate model, end-stage liver disease was associated with older age (38 years and older) at enrollment (adjusted RR, 3.67 [CI, 1.96 to 6.88]) and drinking more than 260 g/week of alcohol (adjusted RR, 3.60 [CI, 1.73 to 7.52]) (68).

  • A prospective cohort study evaluated outcomes in 376 women who were infected with HCV after receiving contaminated immune globulin. After a follow-up time of 17 years, 81% had symptoms, including fatigue in 66%; 2% had probable or definite cirrhosis (69).

  • A 2005 narrative review on the natural history of HCV infection estimated that the rate of development of cirrhosis over 10 to 20 years of HCV infection is between 5% and 25% (33).

Rationale
  • Accurate information about the natural history of hepatitis C should help reduce anxiety and allow for more rational management decisions.

Comments
  • Because long-term progression can be difficult to predict, slow progression should be considered more an argument for safely delaying treatment when appropriate rather than determining that treatment will never be indicated.

  • Evolving understanding of extra-hepatic manifestations of hepatitis C should be considered when counseling the patient and making treatment decisions.

  • Periodic patient monitoring to assess progression and possible complications should occur during any treatment deferral period.

  • With the availability of more effective and safer treatment options, more patients who have mild disease and are at low risk for developing complications from hepatitis C infection should now consider or reconsider treatment.

Review with the patient methods to ameliorate treatment-associated adverse events. 
  • Inform patients that the most common side effects of the direct-acting antiviral agents are nausea, fatigue, headache, insomnia, and pruritus.

  • Alert patients to review current drug regimens to avoid drug-drug interactions with direct-acting antiviral agents.

  • Suggest that pregnancy be avoided with ribavirin whenever possible.

  • Urge patients to report all unexpected adverse events to the treating provider.

  • Inform patients that most adverse events are tolerable and can be managed without drug reductions or discontinuation or major lifestyle changes.

  • Note that most adverse events reverse after discontinuation of therapy.

  • Note that in a small proportion of patients (1% to 2%) receiving interferon-based treatment, hypothyroidism may develop and require lifelong thyroid hormone replacement.

  • Note that symptoms of depression may be exacerbated during interferon-based treatment and generally improve with antidepressant therapy.

  • Recommend that patients take small amounts of acetaminophen or NSAIDs before and after each interferon injection to reduce the flu-like symptoms induced by the drug.

  • Advise the patient to maintain hydration by increasing fluid intake during treatment.

  • Educate patients about the need for possible medication adjustments as well as the possible need for erythropoietin and/or blood transfusions due to the more marked anemia noted in triple therapy.

Evidence
  • Consensus.

Rationale
  • Patients and providers should be aware of the common adverse events and their management.

  • Treatment adherence increases the likelihood of benefit from treatment.

Comments
  • Informed patients and an experienced clinical team are better prepared to deal with anticipated adverse events.

Inform patients about the routes of HCV transmission. 
  • Emphasize the low efficiency of the sexual transmission of HCV.

  • Disclose the fact that the risk for infection between monogamous sexual partners is only 3% to 5% over many years.

  • Emphasize the low risk for transmission of HCV from infected women to their newborns.

  • Advise HCV-infected women with cracked or bleeding nipples to abstain from breastfeeding.

  • Advise patients to avoid sharing personal care implements, such as razor blades, toothbrushes, and nail clippers.

Evidence
  • The National Hepatitis Screening Survey, a cross-sectional screening study, evaluated for the presence of HCV in 14,000 patients from 40 centers across the U.S. The prevalence of HCV was 7%, and 3% of patients had both HCV and hepatitis B infection. Risk factors for HCV included intravenous drug use, blood transfusions, hemodialysis, and having sex with an intravenous drug user (4).

  • A prospective cohort study evaluated rates of HCV and HIV acquisition in 428 injection drug users in England. At baseline, 44% were infected with HCV and 4% with HIV. After 1 year the conversion rate for HCV was 42/100 person-years and for HIV was 3.4/100 person-years (5).

  • A cross-sectional study evaluated rates of blood-borne pathogens in 716 injection drug users. Among patients who had injected for 1 year or less, the prevalence of HCV was 65%, of HBV, 50%, and of HIV, 14%. In the multivariate analysis, HCV infection was independently associated with daily injection (vs. less than daily; OR, 4.40 [CI, 1.01 to 19.10]), injection of any cocaine in the last 6 months (OR, 5.25 [CI, 1.24 to 22.22]), and duration of drug use (OR, 2.14 [CI, 1.17 to 3.94] for more than 6 months compared to less than 6 months of use) (6).

  • A cross-sectional study evaluated rates of HCV in 154 spouses of patients with viremic HCV. Antibodies to HCV were found in 27% of spouses (9).

Rationale
  • Accurate information should reduce patient anxiety.

Comments
  • Sexual transmission and maternal-neonatal transmission do occur, but the risk is low.

Urge patients with chronic hepatitis C to avoid alcohol intake.  
  • Urge patients with HCV infection to discontinue all alcohol consumption.

  • Urge patients with advanced fibrosis to abstain from alcohol use as this accelerates disease progression.

Evidence
  • A retrospective cohort study evaluated the impact of alcohol consumption on clinical status in 120 Japanese patients with chronic liver disease from HCV and/or alcohol. Alcohol consumption did not correlate with serum ALT or HCV RNA levels or with inflammation on histology. However, rates of cirrhosis were lower among patients with HCV who did not drink alcohol (16.9%) than among those who were moderate (47.5%) or heavy (27.2%) drinkers (P<0.01) (52).

  • A prospective cohort study described long-term outcomes in 1667 injection drug users with HCV. After a median follow-up time of 8.8 years, 40 patients developed end-stage liver disease (incidence of 3.1/1000 person years). In the multivariate model, end-stage liver disease was associated with older age (38 years or older) at enrollment (adjusted RR, 3.67 [CI, 1.96 to 6.88]) and drinking more than 260 g/week of alcohol (adjusted RR, 3.60 [CI, 1.73 to 7.52]) (68).

  • A 1997 narrative review of alcohol and HCV noted that alcohol consumption during treatment probably reduces the likelihood of SVR (70).

Rationale
  • Alcohol may accelerate disease progression and may interfere with treatment response.

Comments
  • Although there is no evidence that smaller amounts (<30 g) of alcohol taken on occasion are harmful, it seems reasonable to prohibit daily or weekly alcohol consumption.

Refer patients with hepatitis C to support groups as needed. 
  • Consider referring patients with hepatitis C and their families to support groups.

Evidence
  • Consensus.

Rationale
  • Sharing information with other patients may reduce anxiety.

Comments
  • Controlled studies of the utility of support groups are needed.

During treatment for hepatitis C, obtain blood counts regularly. 
  • Clinic visits or telephone contact are recommended as clinically indicated during treatment to ensure medication adherence and to monitor for adverse events and potential drug-drug interactions with newly prescribed medications.

  • Obtain CBC, creatinine level and calculated GFR, and hepatic function panel after 4 weeks of treatment.

  • Obtain TSH every 12 weeks for patients receiving interferon.

  • Obtain other lab work to assess drug-related toxic effects, including CBC for patients receiving ribavirin.

  • At week 4

    • Discontinue therapy for a 10-fold increase in ALT activity, or for any increased in ALT of less than 10-fold that is accompanied by weakness, nausea, vomiting, or jaundice, or accompanied by increased bilirubin, alkaline phosphatase, or INR.

    • Observe closely any patients with an asymptomatic increase in ALT of less than 10-fold elevated without other lab abnormalities; repeat ALT at week 6 and 8.

  • In patients being treated with interferon-based therapy, check CBC at weeks 1, 2, and 4 and monthly thereafter.

  • See table Elements of Follow-up for Hepatitis C.

Evidence
  • The 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended assessment of ALT level, CBC, creatinine and hepatic levels after 1 month of therapy (11). (Last accessed March 6, 2015.)

  • In a U.S. multicenter randomized trial which compared interferon monotherapy with interferon plus ribavirin, drug discontinuation was necessary in 14% of patients who were treated with interferon monotherapy and in 21% of patients given combination therapy over 48 weeks. Eight percent of patients on combination therapy decreased the dose due to anemia (66).

Rationale
  • Interferon-induced bone marrow suppression and ribavirin-induced hemolytic anemia, which may be exacerbated by the use of protease inhibitors, need to be identified; if necessary, treatment must be modified.

Comments
  • When major reductions in platelets, leukocyte counts, or hemoglobin levels occur, it is often during the first several weeks of treatment.

Periodically monitor thyroid function during treatment with interferon-based regimens.  
  • Measure TSH level at baseline, every 6 months during treatment for hepatitis C, and 6 months after the end of treatment in patients receiving interferon.

  • See table Elements of Follow-up for Hepatitis C.

Evidence
  • A prospective cohort study evaluated the risk for hypothyroidism in 109 patients treated for HCV with interferon-α. Overall, 9 patients (8.3%) developed thyroid disease. The presence of microsomal antibodies was a risk factor for the development of thyroid disease during therapy (71).

Rationale
  • Thyroid dysfunction is common; in a small proportion of patients, permanent hypothyroidism may evolve in patients on interferon.

Monitor HCV RNA count at baseline, during, and after treatment for hepatitis C. 
  • Measure HCV RNA at baseline and:

    • At 4, 12, and 24 weeks

    • For all patients with an end of treatment response, monitor viral load at 12 weeks and, for those with SVR at 12 weeks, at 24 weeks after treatment

    • For patients with SVR at 24 weeks, measure viral load periodically thereafter

  • See table Elements of Follow-up for Hepatitis C.

Evidence
  • The 2014 AASLD/IDSA guideline on testing, managing, and treating hepatitis C recommended obtaining a quantitative HCV viral load test at week 4 with a repeat test at 12 weeks following completion of therapy. Repeat quantitative HCV viral load test if still detectable after 2 additional weeks of treatment. Consider discontinuing treatment if repeat quantitative HCV viral load has increased by greater than 10-fold on repeat testing at week 6 or thereafter (11). (Last accessed March 6, 2015.)

  • A prospective cohort study evaluated outcomes in 80 patients with HCV who had a SVR to therapy. After a mean follow-up time of 4 years, 96% of patients had persistently undetectable levels of HCV (61).

  • A randomized trial compared 24 weeks to 48 weeks of treatment in 322 patients with HCV genotype 1 who had undetectable HCV levels at 4 and 12 weeks on a regimen of telaprevir, pegylated interferon, and ribavirin for 12 weeks followed by pegylated interferon and ribavirin thereafter. SVR rates were similar in both groups and were 92% in the short-therapy group (72).

Rationale
  • RVR (virus-free at 4 weeks) is a predictors of viral eradication.

Comments
  • The significance of a positive HCV RNA test result at week 4 that remains positive, but lower, at week 6 or week 8 is unknown.

Table Grahic Jump Location
 Laboratory and Other Studies for Hepatitis C

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TestSensitivity (%)Specificity (%)Notes
ELISA (third generation)94-10097-99May be falsely negative in immunosuppressed patients or in those on long-term hemodialysis; positive results do not distinguish between acute, chronic, or resolved infection
Point-of-care HCV antibody test: blood98.999.5Rapid tests may be preferred for screening in community settings
Point-of-care HCV antibody test: serum or plasma98.999.7Rapid tests may be preferred for screening in community settings
Point-of-care HCV antibody test: oral fluid97.198.2Rapid tests may be preferred for screening in community settings
HCV RNA PCR9699Costly; needed to confirm diagnosis of active infection
ALT and AST levels~50%LowALT levels are usually less than 10 times the upper reference level
HCV genotypingHighHighCostly; perform if HCV RNA is present; needed to determine specifics of treatment including duration, and may help predict likelihood of response
Imaging studies (ultrasound, CT, and MRI of the liver)Baseline screening ultrasound is often performed, CT or MRI is usually reserved for patients in whom cirrhosis is suspected

ALT = alanine aminotransferase; ANA = antinuclear antibody; ASMA = anti-smooth muscle antibody; AST = aspartate aminotransferase; CBC = complete blood count; CT = computed tomography; ELISA = enzyme-linked immunosorbent assay; HCV = hepatitis C virus; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; RNA = ribonucleic acid.

Table Grahic Jump Location
 Differential Diagnosis of Hepatitis C

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DiseaseCharacteristics
Hepatitis C infectionScreening is recommended in patients at increased risk
Test for anti-HCV; if positive, test for HCV RNA to confirm active infection
Chronic hepatitis B and DEpidemiologic features resemble those of chronic hepatitis C
Test for HBsAg and anti-HBc; if positive, testing for anti-HDV is appropriate. Co-infection may occur with HBV and HCV
Autoimmune hepatitisLargely affects women, other autoimmune disorders may be present
Test for ANA, ASMA, and serum immunoglobulin levels
Drug-induced chronic hepatitisHistory of taking the offending drug and improvement upon discontinuation of drug
Metabolic and genetic disordersIron overload is not usually clinically evident until mid-life (later in women); Wilson's disease is rarely diagnosed after age 40
Testing for iron overload (serum iron level, transferrin saturation, genetic testing, and, if necessary, hepatic iron index based on quantitative measurement of iron in liver biopsy sample); testing for Wilson's disease (serum ceruloplasmin level, serum and urinary copper levels in patients <40, and, if necessary, measurement of hepatic copper concentration in liver biopsy sample); test for α1-antitrypsin deficiency (serum level and phenotype); obtain stain of liver biopsy tissue, if available, for PAS-positive diastase-resistant globules
Alcoholic hepatitisAST level exceeds ALT level in 90% of cases
History of excessive alcohol consumption and improvement upon discontinuation; liver biopsy demonstrates histologic features of alcoholic hepatitis
NASHMay progress to cirrhosis and end-stage liver disease in some patients
Associated with diabetes, obesity, hypertriglyceridemia, and medications including corticosteroids; absence of frequent alcohol use; diagnosed with a liver biopsy

ALT = alanine aminotransferase; ANA = antinuclear antibody; anti-HBc = anti-hepatitis B core antigen; AST = aspartate aminotransferase; HBc = hemoglobin C; HBsAg = hepatitis B surface antigen; HDV = hepatitis D virus; NASH = nonalcoholic steatohepatitis; PAS = periodic acid-Schiff.

Table Grahic Jump Location
 Drug Treatment for Hepatitis C

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Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
Direct-acting antiviral fixed combinationsTreatment regimens are for treatment-naïve patients
Ledipasvir, 90 mg/Sofosbuvir 400 mg (Harvoni)1 tablet PO qd for 12 weeksFatigue, headache, insomnia, nausea, diarrheaNo data with severe CKD. Avoid P-gp inducers. Post-marketing adverse event reports of life-threatening symptomatic bradycardia when amiodarone is taken with sofosbuvir and another direct-acting antiviral agent such as ledipasvirHCV genotype 1a, 1b, 4, or 6
Ombitasvir 12.5 mg, Paritaprevir 75 mg, Ritonavir, 50 mg, Dasabuvir, 250 mg (Viekira)2 ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets qd (in the morning) and 1 dasabuvir, 250 mg tablet bidNausea, pruritus, insomniaAvoid with severe hepatic disease. Avoid with drugs that are highly dependent on CYP3A for clearance; potent inducers of CYP3A and CYP2C8; potent inhibitors of CYP2C8With or without weight-based ribavirin (1000 mg if <75 kg to 1200 mg if >75 kg) divided and administered bid for 12 or 24 weeks for HCV genotype 1A, 1b, or 4
Direct-acting antiviral agentsTreatment regimens are for treatment-naïve patients
Sofosbuvir (Sovaldi)400 mg PO qdFatigue, headache, insomnia, asthenia, flu-like symptoms, nausea, diarrhea, pruritus, rash, hematologic toxicityNo data with severe CKD. Avoid with P-gp inducers. Due to ribavirin, must avoid pregnancy (male and female patients). Post-marketing adverse event reports of life-threatening symptomatic bradycardia when amiodarone is taken with sofosbuvir and another direct-acting antiviral agentCombine with simepravir 150 mg with or without weight-based ribavirin (1000 mg if <75 kg to 1200 mg if ≥75 kg) divided and administered bid for 12 or 24 weeks for HCV genotype 1a or 1b, or as alternative for genotype 4
Combine with weight-based ribavirin (dosing as above) for 12, 16, or 24 weeks for HCV genotype 2, 3. or 4
Alternative for genotype 3, 4, 5, or 6: Combine with weight-based ribavirin (dosing as above) plus weekly PEG-IFN for 12 weeks
Simeprevir (Olysio)150 mg PO qd with food, for an initial 12 weeksRash, pruritus, photosensitivity, dyspnea, nausea, myalgia, hyperbilirubinemiaInhibits CYP3A4. Caution with: CYP3A inducers or inhibitors, sulfa allergy. Elevated drug level in AsiansBefore starting screen for NS3 Q80K polymorphism
Antiviral
blackboxiconRibavirin (Rebetol, Ribasphere, Copegus)1000 mg if <75 kg to 1200 mg if ≥75 kgPsychiatric adverse events, dyspnea, hematologic toxicity, fever, chills, GI side effects, fatigue, arthralgia, myalgia, rash, alopecia, headache, male infertility, menstrual irregularityblackboxicon Do not use as monotherapy for chronic HCV infection. Can cause hemolytic anemia that leads to MI. Avoid pregnancy (male and female patients). Decrease dose or avoid with CKD (depends on formulation). Caution with: CV disease, elderly, thyroid diseaseAlternative for HCV genotype 5: Combine with pegylated interferon-alfa
blackboxiconPegylated interferon-alfaFlu-like symptoms, injection site reactions, GI side effects, hepatotoxicity, dyspnea, allergic reactions, hematologic toxicity, alopecia, pruritus, hearing impairment, neutralizing antibodiesblackboxicon May cause fatal neuropsychiatric, autoimmune, ischemic and infectious disorders. Avoid with: pregnancy, moderate-severe hepatic disease, autoimmune hepatitis. Monitor: LFTs, triglycerides, vision. Caution with: diabetes, elderly, thyroid disease, cardiac disease, pulmonary disease
Discontinue if colitis occurs
blackboxiconPeginterferon-alfa-2a (Pegasys)180 mcg SC once weeklyElevated triglycerides, back painDecrease dose with CrCl<30. Inhibitor of CYP1A2
blackboxiconPeginterferon-alfa-2b (PegIntron)1.5 mcg/kg SC once weeklyNephrotoxicity, menstrual irregularityDecrease dose with CrCl<50. Caution with CYP 2D6 or 2C8/9 substrates

blackboxicon = black box warning; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P450 isoenzyme; GI = gastrointestinal; HCV = hepatitis C virus; IM = intramuscular; IV = intravenous; LFT = liver function test; MI = myocardial infarction; P-gp = P-glycoprotein; PO = oral; q12hr = every 12 hours; qd = once daily; qid = four times daily; SC = subcutaneous; SCr = serum creatinine; tid = three times daily

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 Elements of Follow-up for Hepatitis C

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IssueHow?How Often?Notes
Bone marrow suppressionReview of systems for anemia (fatigue, shortness of breath), neutropenia (infectious symptoms), and thrombocytopenia (easy bruising, bleeding)At each visit
Depression and anxietyPsychiatric review of systemsAt each visit in patients receiving interferon-based therapy
Substance abuseDiscuss alcohol and drug use during treatmentAt each visitThe stress and anxiety of therapy may cause patients with a history of substance abuse to return to these habits
InsomniaReview of systemsAt each visitInsomnia is a common side effect and may be a sign of depression; sleep aids may be necessary
Injection-site reactionSkin examAt each visit in patients receiving interferon-based therapyPatients should be counseled to watch for signs of infection and to rotate injection sites
RashSkin examAt each visitPatients on telaprevir are predisposed to the development of rashes
Progression of liver diseasePhysical exam for ascites, lower extremity edema, and encephalopathyEvery 3 monthsThe development of ascites or encephalopathy indicates decompensated liver disease and should result in the stopping of interferon-based therapies and referral for liver transplant evaluation
PregnancyPregnancy testMonthly while on treatment and for 6 months after the end of treatment if ribavirin is givenRibavirin is a known teratogen; the teratogenicity of interferon is uncertain
Interferon-induced bone marrow suppressionPlatelet, leukocyte, and granulocyte countsAt weeks 1, 2, and 4, then monthly while on interferon-based treatmentReduce dose or discontinue if thrombocytopenia or granulocytopenia is present
Ribavirin-induced hemolytic anemia, which may be exacerbated by protease inhibitorsHemoglobin levelAt weeks 1, 2, and 4, and then monthly while on treatment with ribavirinReduce dose or discontinue if hemoglobin <10 g/dL (or <12 g/dL in patients with cardiac disease)
Thyroid dysfunctionTSH levelEvery 6 months in patients on interferon-based therapyConsider treatment if clinically appropriate
Virologic responseSerum HCV RNAPegylated interferon-α and ribavirin: at weeks 12, 24, 48; if therapy is extended to 48 weeks then also measure at 72 weeks.
For triple therapy with pegylated interferon-α, ribavirin, and telaprevir: at weeks 4, 12, 24, 48; if therapy is extended to 48 weeks then also measure at 72 weeks.
For triple therapy with pegylated interferon-α, ribavirin, and boceprevir: at weeks 4, 8, 12, 24, 48; if therapy is extended to 48 weeks then also measure at 72 weeks
Relapses and nonresponsiveness can be detected at 3 months after interferon monotherapy or at 6 months after combination therapy
Histologic responseLiver biopsyAs neededMay be useful for patients who are virologic nonresponders to reassess stage of disease
Hepatocellular carcinoma in patients with established cirrhosisUltrasoundEvery 6 monthsPatients with cirrhosis are at increased risk for developing hepatocellular carcinoma
Side effectsDiscuss strategies for dealing with side effects, including hydration and interferon premedication with acetaminophen or NSAIDsAt each visit
AdherenceDiscussionAt each visitAdherence may become a major issue because of side effects

ALT = alanine aminotransferase; HCV = hepatitis C virus; NSAID = nonsteroidal anti-inflammatory drug; RNA = ribonucleic acid; TSH = thyroid-stimulating hormone.

Table Grahic Jump Location
 Interpretation of Hepatitis C Virus Testing

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Anti-HCVHCV RNA (PCR)Interpretation
NegativeNegativeNever exposed/no infection
NegativePositiveAcute infection; chronic infection in immunosuppressed
PositivePositiveChronic infection
PositiveNegativeResolved infection (spontaneously or successful treatment)

HCV= hepatitis C virus; PCR = polymerase chain reaction; RNA = ribonucleic acid.

Adapted from (73).

Table Grahic Jump Location
 Examples of HCV Treatment Regimens*

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Genotype†First Choice Drug Regimens (All Equivalent)Alternative Regimens
1A Noncirrhotic treatment-naïveDaily sofosbuvir (400 mg)/ledipasvir (90mg) for 12 weeks
OR
Sofosbuvir (400 mg) plus simeprevir (150 mg) with or without ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) for 12 weeks
OR
Daily paritaprevir 150mg/ritonavir 100mg/ombitasvir 25mg + twice daily dasabuvir 250mg plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg)divided into 2 daily doses for 12 weeks
1A Cirrhotic treatment-naïveSofosbuvir (400 mg) plus simeprevir (150 mg) with or without RBV 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 24 weeks
OR
Daily paritaprevir 150mg/ ritonavir 100mg/ombitasvir 25mg + dasabuvir 250mg bid plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 24 weeks
1A Noncirrhotic treatment-experiencedDaily sofosbuvir (400 mg)/ledipasvir (90mg) for 12 weeks
OR
Daily paritaprevir 150mg/ritonavir 100mg/ombitasvir 25mg + dasabuvir 250mg bid plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 12 weeks
OR
Sofosbuvir (400 mg) plus simeprevir (150 mg) with or without ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 12 weeks
1A Cirrhotic treatment-experiencedDaily sofosbuvir (400 mg)/ledipasvir (90mg) for 24 weeks
OR
Daily sofosbuvir (400 mg)/ledipasvir (90mg) plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 12 weeks
OR
Daily paritaprevir 150mg + ritonavir 100mg + ombitasvir 25mg + dasabuvir 250mg plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 24 weeks
OR
Sofosbuvir (400 mg) plus simeprevir (150 mg) with or without ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 24 weeks
1B Noncirrhotic treatment-naiveDaily sofosbuvir (400 mg)/ledipasvir (90mg) for 12 weeks
OR
Sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks
OR
Daily paritaprevir 150mg/ritonavir 100mg/ ombitasvir 25mg + twice daily dasabuvir 250mg for 12 weeks
1B Cirrhotic treatment-naiveSofosbuvir (400 mg) plus simeprevir (150 mg) for 24 weeks
OR
Daily paritaprevir 150mg/ ritonavir 100mg/ombitasvir 25mg + twice daily dasabuvir 250mg with ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) for 12 weeks
Daily sofosbuvir (400 mg)/ledipasvir (90mg) for 12 weeks (possibly effective in patients with cirrhosis)
1B Noncirrhotic treatment-experiencedDaily sofosbuvir (400 mg)/ledipasvir (90mg) for 12 weeks
OR
Daily paritaprevir 150mg/ ritonavir 100mg/ombitasvir 25mg + twice daily dasabuvir 250mg for 12 weeks
OR
Sofosbuvir (400 mg) plus simeprevir (150 mg) with or without ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 12 weeks
1B Cirrhotic treatment- experiencedDaily sofosbuvir (400 mg)/ledipasvir (90mg) for 24 weeks
OR
Daily sofosbuvir (400 mg)/ledipasvir (90mg) plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 12 weeks
OR
Sofosbuvir (400 mg) plus simeprevir (150 mg) with or without ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 24 weeks
OR
Daily paritaprevir 150mg/ ritonavir 100mg/ombitasvir 25mg + twice daily dasabuvir 250mg plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 12 weeks
2 NoncirrhoticDaily sofosbuvir (400 mg) plus RBV 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 12 weeks
2 CirrhoticDaily sofosbuvir (400 mg) plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 16 weeks
3Daily sofosbuvir (400 mg) plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 24 weeksDaily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks
4Daily sofosbuvir (400 mg)/ledipasvir (90mg) for 12 weeks
OR
Daily paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks
OR
Daily sofosbuvir (400 mg) plus ribavirin 1000 mg (<75kg) or 1200mg (≥75kg) divided into 2 daily doses for 24 weeks
Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks
CellTxtL::CellTxtL::CellTxtL::OR
CellTxtL::CellTxtL::CellTxtL::(treatment-naïve only) Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks
5Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeksWeekly pegylated interferon plus weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 48 weeks
5Daily sofosbuvir (400 mg) plus weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeksWeekly pegylated interferon plus weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 48 weeks
6Daily sofosbuvir (400 mg)/ledipasvir (90 mg) for 12 weeksDaily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks
6Daily sofosbuvir (400 mg)/ledipasvir (90 mg) for 12 weeksDaily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks

* Based on genotype, extent of liver fibrosis, and history of treatment.

† When relevant, also extent of fibrosis and/or prior history of treatment. Otherwise appropriate for all patients with subtype.

Adapted from AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Initial Treatment Box. Summary of Recommendations for Patients Who are Initiating Therapy for HCV Infection by HCV Genotype and Retreatment of Persons in Whom Prior therapy has Failed.

  • Hepatitis C-Associated Cryoglobulinemia Hepatitis C-associated cryoglobulinemia presenting as abdominal purpura.
  • Hepatitis C-Associated Porphyria Cutanea Tarda Cutaneous porphyria cutanea tarda commonly presents as a chronic blistering skin disease on sun exposed skin, especially the back of the hands.
  • Hepatitis C Histology Hepatitis C biopsy specimen prepared with connective tissue stain showing stage I fibrosis.
  • Lichen Planus Involving Buccal Mucosa Lichen planus is an autoimmune disease of unknown cause that can affect the skin, mucous membranes, scalp, or nails. Common clinical findings of mucosal lichen planus are a white reticulated network on the buccal mucosa (Wickham striae); desquamative gingivitis; and chronic, painful erosions on the oral or vulvar mucosa.
Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64:1-137. (PMID: 26042815)
 
Hagan H, Pouget ER, Des Jarlais DC. A systematic review and meta-analysis of interventions to prevent hepatitis C virus infection in people who inject drugs. J Infect Dis. 2011;204:74-83. (PMID: 21628661)
 
Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-14. [Full Text] (PMID: 16702586)
 
Kaur S, Rybicki L, Bacon BR, Gollan JL, Rustgi VK, Carey WD. Performance characteristics and results of a large-scale screening program for viral hepatitis and risk factors associated with exposure to viral hepatitis B and C: results of the National Hepatitis Screening Survey. National Hepatitis Surveillance Group. Hepatology. 1996;24:979-86. (PMID: 8903363)
 
Judd A, Hickman M, Jones S, McDonald T, Parry JV, Stimson GV, et al. Incidence of hepatitis C virus and HIV among new injecting drug users in London: prospective cohort study. BMJ. 2005;330:24-5. (PMID: 15533854)
 
Garfein RS, Vlahov D, Galai N, Doherty MC, Nelson KE. Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. Am J Public Health. 1996;86:655-61. (PMID: 8629715)
 
Conry-Cantilena C, VanRaden M, Gibble J, Melpolder J, Shakil AO, Viladomiu L, et al. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med. 1996;334:1691-6. (PMID: 8637513)
 
Lin JS, Whitlock E, O’Connor E, Bauer V. Behavioral counseling to prevent sexually transmitted infections: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149:497-508, W96-9. [Full Text] (PMID: 18838730)
 
Akahane Y, Kojima M, Sugai Y, Sakamoto M, Miyazaki Y, Tanaka T, et al. Hepatitis C virus infection in spouses of patients with type C chronic liver disease. Ann Intern Med. 1994;120:748-52. [Full Text] (PMID: 8147548)
 
Henning KJ, Bell E, Braun J, Barker ND. A community-wide outbreak of hepatitis A: risk factors for infection among homosexual and bisexual men. Am J Med. 1995;99:132-6. (PMID: 7625417)
 
AASLD/IDSA HCV Guidance Panel. Hepatitis C Guidance: AASLD-IDSA Recommendations for Testing, Managing, and Treating Adults Infected with Hepatitis C Virus. Hepatology. 2015 06 25 [Epub ahead of print]. (PMID: 26111063)
 
Peña-Orellana M, Hernández-Viver A, Caraballo-Correa G, Albizu-García CE. Prevalence of HCV risk behaviors among prison inmates: tattooing and injection drug use. J Health Care Poor Underserved. 2011;22:962-82. (PMID: 21841290)
 
Polish LB, Tong MJ, Co RL, Coleman PJ, Alter MJ. Risk factors for hepatitis C virus infection among health care personnel in a community hospital. Am J Infect Control. 1993;21:196-200. (PMID: 7694529)
 
Datta SD, Armstrong GL, Roome AJ, Alter MJ. Blood exposures and hepatitis C virus infections among emergency responders. Arch Intern Med. 2003;163:2605-10. (PMID: 14638560)
 
Puro V, Petrosillo N, Ippolito G. Risk of hepatitis C seroconversion after occupational exposures in health care workers. Italian Study Group on Occupational Risk of HIV and Other Bloodborne Infections. Am J Infect Control. 1995;23:273-7. (PMID: 8585637)
 
Moyer VA; U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: u.s. Preventive services task force recommendation statement. Ann Intern Med. 2013;159:349-57. [Full Text] (PMID: 23798026)
 
Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2013;157:817-22. [Full Text] (PMID: 22910836)
 
Chou R, Cottrell EB, Wasson N, Rahman B, Guise JM. Screening for hepatitis C virus infection in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158:101-8. [Full Text] (PMID: 23183613)
 
Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012;156:263-70. [Full Text] (PMID: 22056542)
 
McGarry LJ, Pawar VS, Panchmatia HR, Rubin JL, Davis GL, Younossi ZM, et al. Economic model of a birth cohort screening program for hepatitis C virus. Hepatology. 2012;55:1344-55. (PMID: 22135116)
 
Coffin PO, Scott JD, Golden MR, Sullivan SD. Cost-effectiveness and population outcomes of general population screening for hepatitis C. Clin Infect Dis. 2012;54:1259-71. (PMID: 22412061)
 
Centers for Disease Control and Prevention (CDC). Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62:362-5. (PMID: 23657112)
 
Shivkumar S, Peeling R, Jafari Y, Joseph L, Pant Pai N. Accuracy of Rapid and Point-of-Care Screening Tests for Hepatitis C: A Systematic Review and Meta-analysis. Ann Intern Med. 2012;157:558-66. [Full Text] (PMID: 23070489)
 
Chou R, Clark EC, Helfand M; U.S. Preventive Services Task Force. Screening for hepatitis C virus infection: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2004;140:465-79. [Full Text] (PMID: 15023713)
 
Colin C, Lanoir D, Touzet S, Meyaud-Kraemer L, Bailly F, Trepo C; HEPATITIS Group. Sensitivity and specificity of third-generation hepatitis C virus antibody detection assays: an analysis of the literature. J Viral Hepat. 2001;8:87-95. (PMID: 11264728)
 
de Medina M, Hill M, Sullivan HO, Leclerq B, Pennell JP, Jeffers L, et al. Detection of anti-hepatitis C virus antibodies in patients undergoing dialysis by utilizing a hepatitis C virus 3.0 assay: correlation with hepatitis C virus RNA. J Lab Clin Med. 1998;132:73-5. (PMID: 9665375)
 
Preiksaitis JK, Cockfield SM, Fenton JM, Burton NI, Chui LW. Serologic responses to hepatitis C virus in solid organ transplant recipients. Transplantation. 1997;64:1775-80. (PMID: 9422419)
 
George SL, Gebhardt J, Klinzman D, Foster MB, Patrick KD, Schmidt WN, et al. Hepatitis C virus viremia in HIV-infected individuals with negative HCV antibody tests. J Acquir Immune Defic Syndr. 2002;31:154-62. (PMID: 12394793)
 
Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333-42. (PMID: 23172780)
 
Dubois F, Desenclos JC, Mariotte N, Goudeau A. Hepatitis C in a French population-based survey, 1994: seroprevalence, frequency of viremia, genotype distribution, and risk factors. The Collaborative Study Group. Hepatology. 1997;25:1490-6. (PMID: 9185773)
 
Bellentani S, Pozzato G, Saccoccio G, Crovatto M, Crocè LS, Mazzoran L, et al. Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study. Gut. 1999;44:874-80. (PMID: 10323892)
 
Alberti A, Noventa F, Benvegnù L, Boccato S, Gatta A. Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection. Ann Intern Med. 2002;137:961-4. [Full Text] (PMID: 12484711)
 
Thomas DL, Seeff LB. Natural history of hepatitis C. Clin Liver Dis. 2005;9:383-98, vi. (PMID: 16023972)
 
Andrade LJ, D’Oliveira A, Silva CA, Nunes P, França LS, Malta AM, et al. A meta-analysis of patients with chronic hepatitis C treated with interferon-gammalpha to determine the risk of autoimmune thyroiditis. Acta Gastroenterol Latinoam. 2011;41:104-10. (PMID: 21894723)
 
Ferri C, Sebastiani M, Giuggioli D, Cazzato M, Longombardo G, Antonelli A, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004;33:355-74. (PMID: 15190522)
 
Adinolfi LE, Utili R, Attanasio V, Zampino R, Ragone E, Tripodi MF, et al. Epidemiology, clinical spectrum and prognostic value of mixed cryoglobulinaemia in hepatitis C virus patients: a prospective study. Ital J Gastroenterol. 1996;28:1-9. (PMID: 8743066)
 
Vallisa D, Bertè R, Rocca A, Civardi G, Giangregorio F, Ferrari B, et al. Association between hepatitis C virus and non-Hodgkin's lymphoma, and effects of viral infection on histologic subtype and clinical course. Am J Med. 1999;106:556-60. (PMID: 10335728)
 
Mason AL, Lau JY, Hoang N, Qian K, Alexander GJ, Xu L, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;29:328-33. (PMID: 9918906)
 
Curry MP. Hepatitis B and hepatitis C viruses in liver transplantation. Transplantation. 2004;78:955-63. (PMID: 15480158)
 
Kamar N, Izopet J, Alric L, Guilbeaud-Frugier C, Rostaing L. Hepatitis C virus-related kidney disease: an overview. Clin Nephrol. 2008;69:149-60. (PMID: 18397713)
 
Charles ED, Dustin LB. Hepatitis C virus-induced cryoglobulinemia. Kidney Int. 2009;76:818-24. (PMID: 19606079)
 
Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA. 2007;297:724-32. (PMID: 17312292)
 
Cheung RC. Epidemiology of hepatitis C virus infection in American veterans. Am J Gastroenterol. 2000;95:740-7. (PMID: 10710068)
 
Zein NN. Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev. 2000;13:223-35. (PMID: 10755999)
 
Marcellin P. Hepatitis C: the clinical spectrum of the disease. J Hepatol. 1999;31 Suppl 1:9-16. (PMID: 10622554)
 
McGill DB, Rakela J, Zinsmeister AR, Ott BJ. A 21-year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology. 1990;99:1396-400. (PMID: 2101588)
 
Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol. 1986;2:165-73. (PMID: 3958472)
 
Wong JB, Bennett WG, Koff RS, Pauker SG. Pretreatment evaluation of chronic hepatitis C: risks, benefits, and costs. JAMA. 1998;280:2088-93. (PMID: 9875876)
 
Arora S, Thornton K, Murata G, Deming P, Kalishman S, Dion D, et al. Outcomes of treatment for hepatitis C virus infection by primary care providers. N Engl J Med. 2011;364:2199-207. (PMID: 21631316)
 
Murray KF, Carithers RL; AASLD. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. 2005;41:1407-32. (PMID: 15880505)
 
Cholongitas E, Marelli L, Shusang V, Senzolo M, Rolles K, Patch D, et al. A systematic review of the performance of the model for end-stage liver disease (MELD) in the setting of liver transplantation. Liver Transpl. 2006;12:1049-61. (PMID: 16799946)
 
Khan KN, Yatsuhashi H. Effect of alcohol consumption on the progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients. Alcohol Alcohol. ;35:286-95. (PMID: 10869250)
 
Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of Hepatitis C Virus Infection and the Development of Hepatocellular Carcinoma: A Meta-analysis of Observational Studies. Ann Intern Med. 2013;158:329-37. [Full Text] (PMID: 23460056)
 
Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med. 2000;132:296-305. [Full Text] (PMID: 10681285)
 
Smith MA, Chan J, Mohammad RA. Ledipasvir-Sofosbuvir: Interferon-gammaRibavirin-Free Regimen for Chronic Hepatitis C Virus Infection. Ann Pharmacother. 2015;49:343-350. (PMID: 25515863)
 
Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, et al.; PEARL-IV Study. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-92. (PMID: 24795200)
 
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al.; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879-88. (PMID: 24720702)
 
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-87. (PMID: 23607594)
 
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, et al.; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211-21. (PMID: 24428467)
 
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al.; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-77. (PMID: 23607593)
 
Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127:875-81. [Full Text] (PMID: 9382365)
 
Lau DT, Kleiner DE, Ghany MG, Park Y, Schmid P, Hoofnagle JH. 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology. 1998;28:1121-7. (PMID: 9755252)
 
Vento S, Garofano T, Renzini C, Cainelli F, Casali F, Ghironzi G, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med. 1998;338:286-90. (PMID: 9445408)
 
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al.; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-93. (PMID: 24725238)
 
Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014;146:430-41.e6. (PMID: 24184810)
 
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. interferon-α-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-92. (PMID: 9819446)
 
Seeff LB, Miller RN, Rabkin CS, Buskell-Bales Z, Straley-Eason KD, Smoak BL, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med. 2000;132:105-11. [Full Text] (PMID: 10644270)
 
Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284:450-6. (PMID: 10904508)
 
Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med. 1999;340:1228-33. (PMID: 10210705)
 
Schiff ER. Hepatitis C and alcohol. Hepatology. 1997;26:39S-42S. (PMID: 9305662)
 
Watanabe U, Hashimoto E, Hisamitsu T, Obata H, Hayashi N. The risk factor for development of thyroid disease during interferon-alpha therapy for chronic hepatitis C. Am J Gastroenterol. 1994;89:399-403. (PMID: 8122653)
 
Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al.; ILLUMINATE Study Team. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-24. (PMID: 21916639)
 
Leigh JP, Bowlus CL, Leistikow BN, Schenker M. Costs of hepatitis C. Arch Intern Med. 2001;161:2231-7. (PMID: 11575980)
 
AASLD

American Association for the Study of Liver Disease

ALT

alanine aminotransferase

ANA

antinuclear antibody

anti-HBc

anti-hepatitis B core antigen

anti-HBs

anti-hepatitis B surface antigen

ASMA

anti-smooth muscle antibody

AST

aspartate aminotransferase

CAD

coronary artery disease

CBC

complete blood (cell) count

CT

computed tomography

d

daily

ELISA

enzyme-linked immunosorbent assay

FDA

Food and Drug Administration

GGT

gamma-glutamyl transpeptidase

GI

gastrointestinal

HBc

hepatitis B core antibody

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HCV

hepatitis C virus

HDV

hepatitis D virus

HIV

human immunodeficiency virus

IDSA

Infectious Diseases Society of America

IL28b

interleukin 28b

IU

international units

MELD

Model for End-Stage Liver Disease (score)

MU

million units

NAFL

nonalcoholic fatty liver

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NSAID

nonsteroidal anti-inflammatory drug

po

oral

QALY

Quality-adjusted life year

RIBA

recombinant immunoblot assay

RNA

ribonucleic acid

RVR

rapid virologic response

sc

subcutaneous

SVR

sustained virologic response

TSH

thyroid-stimulating hormone


DOI: 10.7326/d163
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Author(s) and Disclosures:
Raymond S. Koff, MD has nothing to disclose. Andrew Muir, MD received honorarium from Schering Plough, is part of speakers bureau of Schering Plough, received grants from Schering Plough, and has grants pending from Roche. Donald Gardenier, DNP, FNP, FAANP, FAAN has nothing to disclose.

One or more of the present or past ACP Smart Medicine physician editors worked on this module and had nothing to disclose: Davoren Chick, MD, FACP; Deborah Korenstein, MD, FACP; Marjorie Lazoff, MD; Richard Lynn, MD, FACP.

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