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Hepatitis C in 2014:

Don't Miss the Diagnosis!

Chronic hepatitis C virus (HCV) infection affects about 3.2 million people in the United States1 and is the primary cause of chronic liver failure.2,3 HCV is the most common bloodborne infection, and the highest transmission rates occur in people with a history of intravenous drug abuse. After initial infection with HCV, 75% to 80% of patients develop chronic infection. Twenty percent of these patients develop cirrhosis within 20 years.1 More than 16,000 people die each year from complications of HCV, making it the 12th leading cause of death in this country.4

Epidemiologic studies show that people born between 1945 and 1965 have the highest incidence of HCV, accounting for about 75% of those infected.5­­ This age group was likely exposed to HCV in the late 1970s and early 1980s, during peak infection rates.5

In June 2013, the U.S. Preventive Services Task Force recommended birth cohort screening for HCV infection,5 as well as continued screening of people with identified risk factors for HCV exposure:1

·         Born between 1945 and 1965

·         History of intravenous or intranasal drug use

·         History of blood transfusion before 1990

·         History of receiving clotting factors before 1987

·         History of piercing or tattoo with improperly sterilized equipment (including multiuse tattoo inkwells)

·         History of needlestick injury with HCV-positive or HCV-status unknown contaminated needle

·         History of HIV infection

·         Having been born to a HCV-positive mother

·         Long-term sexual partners of HCV-positive individuals

·         Patient's request.

Because HCV often causes no symptoms,1 it is essential that providers obtain a focused history and accurately diagnose HCV infection. This article presents an overview of the current status of HCV assessment and treatment, highlighting key history and diagnostic data necessary to make the diagnosis.

Case Study

The following case study is an example of a typical presentation that a primary care provider might see in his or her clinic:

Mr. H, a 50-year-old white man, tested positive for HCV antibody on age-cohort screening during an annual primary care visit. He has no significant past medical history and has never been diagnosed with liver disease. He reports no abdominal pain, joint pain, clay-colored stools, malaise, fever/chills, nausea or vomiting. He reports no history of jaundice.

Upon detailed questioning, Mr. H reveals that he had a tattoo while on military deployment and snorted cocaine once. He says he has never used intravenous drugs. He drinks two to three beers each weekend, and he quit smoking in 1994.

Mr. H's vital signs are stable, and his physical exam is unremarkable. No hepatomegaly or jaundice is evident. Laboratory data show mildly elevated liver enzymes: aspartate aminotransferase (AST) 44, alanine aminotransferase (ALT) 70, alkaline phosphatase 172, and total bilirubin 1.0. Complete blood count (CBC), electrolyte and renal function tests show no abnormalities. Additional investigation reveals that he is infected with HCV genotype 1a, with a viral load of 978,670 IU (5.991 log).


Hepatitis C virus was first isolated in the mid-1980s, and the first commercial blood test for HCV antibody was developed by 1990.6 The novel virus was discovered while investigating a viral etiology dubbed "non-A, non-B viral hepatitis," which was attributed to more than 90% of transfusion-associated hepatitis cases.7 Since then, 6 HCV genotypes (labeled 1 through 6) have been recognized. In North America and Europe, genotype 1 is the most prevalent, and until recently, one of the least likely genotypes to respond to treatment.1

Chronic HCV infection is defined by the detection of HCV RNA in blood; however, due to the high expense of this test, the cheaper HCV antibody test is often used for screening purposes.8 After initial infection, approximately 20% of people spontaneously clear the virus, determined via detection of anti-HCV antibody, no detectable HCV RNA in the serum, and lack of history of anti-HCV treatment.4 Symptoms of acute infection (fatigue, abdominal pain, decreased appetite and jaundice) present in only about 20% to 30% of all people.1

HCV is a bloodborne pathogen. Infection routes include a history of blood transfusion prior to 1990, receiving clotting factors prior to 1987, a history of intravenous or intranasal drug use, being born to an HCV-positive mother, tattoos or piercings with improper sterilization techniques, and needlestick injuries. HCV may also be spread through shared razors or sexual contact, but these risks of transmission are low.1, 9 Due to a lack of symptoms, many people (like Mr. H) are unaware of their HCV infection. Hepatitis C is usually discovered when routine blood tests reveal elevated liver enzymes or when a patient presents for care with symptoms of end-stage liver disease.1

After diagnosing chronic HCV infection, additional tests are recommended. Up to 8% people with HCV are coinfected with human immunodeficiency virus (HIV),10 and among this group, HCV-related liver disease is the primary cause of non-AIDS mortality.11 For patients with chronic liver disease, the CDC recommends hepatitis B and hepatitis A vaccination, and therefore serologic testing for previous immunity before vaccination may be indicated.

Treatment for HCV has been available since before the virus was isolated. In 1986, interferon-alpha was used to treat non-A, non-B hepatitis. Unfortunately, efficacy was poor, with only 6% of cases successfully treated.12

In the 1990s, the pharmaceutical formulation was improved by binding it to polyethylene glycol (PEG; pegylation), reducing drug metabolism. By improving its half-life, dosing frequency was reduced from three times weekly to once weekly. Adding ribavirin (Copegus, Ribapak) further improved efficacy to about 40% for genotype 1, when taken for 48 weeks.8,11 Genotypes 2 and 3 were slightly easier to eradicate using these two drugs, with efficacy estimated at 76%. However, a 24- to 48-week course of treatment was still recommended.8

Along with weak efficacy, pegylated interferon (Pegasys, Peg-Intron) plus ribavirin therapies have side effects that often result in poor adherence. Interferon therapy can induce depression, anxiety, psychosis and suicidal or homicidal ideation (or worsen pre-existing psychiatric illness). Other side effects of interferon include severe autoimmune-type reactions (i.e., optic neuritis, thyroid storm, pancreatitis, etc.), neutropenia, thrombocytopenia, appetite loss and flu-like illness.13 In addition, pegylated interferon is self-administered subcutaneously, which can be problematic for recovering addicts and in those who fear needles.

Ribavirin is known to cause severe anemia. It is renally cleared, so it is not easily tolerated in patients with renal dysfunction or renal failure, even with dose adjustments.13 Ribavirin is also pregnancy category X; significant teratogenic effects and fetal death have been shown in animal studies.8 Hence, interferon- and ribavirin-based HCV treatment has limited use in certain populations, and is only recommended for patients with evidence of progressing fibrosis.8

Left untreated, HCV infection can lead to liver fibrosis and cirrhosis. The liver biopsy is the current gold standard for determining liver fibrosis.8 However, it is susceptible to sampling error and intraobserver variability (as much as 33% inaccuracy and 14% missed diagnosis of cirrhosis).14 Moreover, liver biopsy is associated with the risk of hemorrhage, requiring blood transfusion, surgery and potentially leading to death.15 Various noninvasive tests have been developed, but they have reduced accuracy and limited use.16 Advanced fibrosis may be suspected based on routine testing via a combination of unexplained thrombocytopenia, hypoalbuminemia, elevated total bilirubin, coagulopathy, or a nodular liver contour on imaging.

When taken in conjunction with history and physical exam, labs and abdominal imaging (i.e., ultrasound, contrast-enhanced MRI or CT) may be sufficient to establish a diagnosis of cirrhosis.

Luckily, HCV treatments are evolving quickly. In April 2011, the first direct-acting antivirals were approved by the FDA: teleprevir (Incivek) and boceprevir (Victrelis). Adding one of these two protease inhibitors to treatment with pegylated interferon and ribavirin increased efficacy from 40% to 70%.12 Unfortunately, both of these medications had many significant drug-drug interactions and decreased tolerability of pegylated interferon and ribavirin.

Simeprevir (Olysio), a second-generation protease inhibitor, was cleared for marketing in November 2013, and it offered the advantage of fewer drug interactions and fewer side effects. But it still requires coadministration with pegylated interferon and ribavirin.17

Treatment was modified again in December 2013, with the approval of the first polymerase inhibitor, sofosbuvir (Sovaldi). Sofosbuvir demonstrated comparatively few side effects and drug-drug interactions, and it is the first interferon-free treatment for HCV genotypes 2 and 3. Sofosbuvir also dramatically shortened treatment duration for genotypes 1 and 4 when taken in conjunction with pegylated interferon and ribavirin (12 weeks). With this new regimen, response rates topped 90% for previously untreated genotypes 2 and 3, and 80% for genotype 1.18

Many new drugs for HCV treatment are being studied in late-phase clinical trials, and it has been estimated that interferon-free treatments for genotypes other than 2 and 3 may be available as early as 2015. Most of these treatments involve coadministration of protease and polymerase inhibitors, and preliminary reports show efficacy upwards of 95% for genotype 1 infection.19,20 Knowing this, many providers are warehousing patients with little to no liver fibrosis, and only recommending HCV treatment for people are at risk for liver failure before these new treatments to become available.

Back to Mr. H

Once HCV infection is established, most primary care providers elect to refer patients to a hepatitis specialist to determine degree of liver fibrosis and candidacy for HCV treatment. Meanwhile, the primary care provider can counsel about Mr. H's modifying risk factors. His alcohol intake should be addressed. In patients with HCV, moderate drinking is associated with increased likelihood of developing liver fibrosis and early progression to cirrhosis.21 Mr. H should be advised to abstain from all alcohol consumption and referred to an alcohol rehabilitation center if needed. HIV screening should be performed,1 and immunity to hepatitis B virus (HBV) and hepatitis A virus (HAV) should be assessed. When a patient is nonimmune to HAV and HBV, vaccination should be given.22,23

Primary care providers can also prepare Mr. H for HCV treatment by screening for and treating psychiatric disease and optimizing control over any inflammatory or autoimmune conditions. Any co-existing conditions that decrease tolerance of anemia should be thoroughly evaluated and treated if possible. For patients without advanced fibrosis who are not receiving HCV treatment, frequent monitoring is not needed. However, to assess for progression of liver disease, yearly CBC and comprehensive metabolic panel are reasonable. Any evidence of cirrhosis or hepatic impairment should prompt referral to a hepatology specialist.

Annual medical care for chronic infection costs an average of $17,277 per year for people with minimal disease to almost $60,000 per year for those with end-stage liver disease.24 For patients with end-stage liver disease, the current national average waiting time to liver transplant is just over 1 year.2 The cost of a liver transplant is estimated at $316,900 to $500,000 per person.25 Therefore, early diagnosis and treatment of HCV are necessary to improve patient outcomes and contain healthcare costs.

Most people with HCV are unaware of their infection,5 so it is the responsibility of the primary care provider to recommend and offer screening to at-risk populations. When HCV is diagnosed early, measures can be taken to reduce the risk of developing cirrhosis and prevent further complications. HCV treatment regimens are evolving quickly and becoming increasingly efficacious with fewer side effects, which will reduce disease burden and lower health care costs.

Janet Gripshover is a nurse practitioner in the Department of Gastroenterology/Hepatology at the University of Maryland Medical Center in Baltimore. This work was supported in part by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the author alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.


1. Center for Disease Control and Prevention. Hepatitis C FAQs for Health Professionals.

2. Organ Procurement and Transplan­tation Network and Scientific Registry of Transplant Recipients. OPTN/SRTR 2011 Annual Data Report. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation; 2012: 73-81.

3. Kim WR. The Burden of Hepatitis C in the United States. Hepatology. 2002;36(5 Suppl 1):S30-S34.

4. Center for Disease Control and Prevention Surveillance for Viral Hepatitis- United States, 2011.

5. U.S. Preventive Services Task Force. Screening for Hepatitis C Virus Infection in Adults: Final Recommendation Statement. AHRQ Publication No. 12-05174-EF-2.

6. Houghton M. Discovery of the hepatitis C virus. Liver Int. 2009;29(Suppl 1):82-88.

7. Kuo G, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989;244(4902):362-364.

8. Ghany MG, et al; for American Association for the Study of Liver Disease. Diagnosis, Management, and Treatment of Hepatitis C: an Update [AASLD Practice Guideline].

9. Terrault NA, et al. Sexual transmission of hepatitis C virus among monogamous heterosexual couples: The HCV Partners Study. Hepatology. 2013;57(3):881-889.

10. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

11. Strader DB, Seeff LB. A Brief History of the Treatment of Viral Hepatitis C. Clin Liver Dis. 2012;1(1):6-11.

12. Grogan A, Timmins F. Side effects of treatment in patients with hepatitis C - implications for nurse specialist practice. Austral J Adv Nurs. 2009;27(2):70-77.

13. Brennan BJ, et al. Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment. Antimicrob Agents Chemother. 2013;57(12):6097-6105.

14. Regev A, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J of Gastroenterol. 2002;97(10):2614-2618.

15. Rockey DC, et al; for American Association for the Study of Liver Disease. Liver Biopsy.

16. Rockey DC, Bissell DM. Noninvasive measures of liver fibrosis. Hepatology. 2006;43:S113-S120.

17. Olysio [package insert]. Janssen Therapeutics, Titusville, NJ; 2013.

18. Sovaldi [package insert] Gilead­­­ Sciences, Inc. Foster City, CA; 2013.

19. Gilead Announces SVR12 Rates From Three Phase 3 Studies Evaluating a Once-Daily Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients. [press release]

20. Abbvie Demonstrates 96 percent SVR(12) in its Phase III Study of Treatment-Experienced Patients with Genotype1 Hepatitis C. [press release]

21. Younossi ZM, et al. Moderate, excessive or heavy alcohol consumption: each is significantly associated with increased mortality in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2013;37(7):703-709.

22. Center for Disease Control and Prevention. Hepatitis A FAQs for Health Professionals.

23. Center for Disease Control and Prevention. Hepatitis B FAQs for Health Professionals.

24. Henry Ford Health System. Economic Cost of Advanced Liver Disease. Science Daily.

25. Hauboldt RH, Hanson SG; for Millman Inc. 2008 U.S. Organ and Tissue Transplant Cost Estimates and Discussion.  


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