How Should I Approach the Management of This Man's Hepatitis C?

You see a 55-year-old married university professor for a routine preventive visit. His past medical history is notable only for hypertension treated with hydrochlorothiazide. He has no history of intravenous drug abuse or blood transfusions.

Should this patient be screened for hepatitis C virus (HCV)?

Yes, screening for HCV is indicated by the 2013 recommendations of the US Preventive Services Task Force (USPSTF). In its statement, the USPSTF concluded with “moderate certainty that screening for HCV infection in adults at increased risk for infection and one-time screening in adults in the 1945-1965 birth cohort has moderate net benefit.”¹ The rationale for screening the boomer birth cohort was based on data from 1999 to 2008 indicating that three-fourths of US patients living with hepatitis C infection were born between 1945 and 1965.

The patient tests positive for antibody to HCV by enzyme immunoassay. Is a confirmatory test needed? If so, what test would you order?

Testing with HCV polymerase chain reaction (PCR) is needed to confirm hepatitis C infection. The sensitivity and specificity of the third generation enzyme-linked immunosorbent assay (EIA) in a high-risk population for hepatitis C infection is 97.2% and nearly 100%, respectively, which is very accurate.

However, among patients with a low prevalence of hepatitis C — such as volunteer blood donors, persons in the general population, and healthcare workers &mdash; the US Centers for Disease Control and Prevention (CDC) has determined that even a high specificity does not provide the desired predictive value for a positive test.² In fact, a false-positive result with the third generation EIA averages nearly 35% among those low-prevalence patients. Therefore, the CDC recommends supplemental testing of all patients who screen positive for hepatitis C via EIA antibody testing to confirm infection. PCR assays, which now have a lower detection limit at approximately <50 IU/ml, are highly sensitive and can directly detect HCV RNA in the patient’s sera to confirm the presence of infection.

HCV RNA PCR is ordered and found to be positive. What tests should be ordered now?

It is important to determine the extent of liver disease in patients diagnosed with hepatitis C infection. Therefore, standard tests should include a hepatic panel, hematologic panel, and prothrombin time in order to assess liver function. Often, a baseline abdominal ultrasound is helpful to determine liver morphology and to assess for presence of portal hypertension indicative of advanced liver disease. Determining hepatitis C genotype is important in deciding whether or not to treat the patient, since HCV genotype 1 responds less favorably to interferon-based regimens compared to genotypes 2 or 3.

What is the natural history of chronic hepatitis C?

More than 90% of patients acquiring acute hepatitis C infection will progress to chronic infection. In cohort studies, it has been estimated that approximately 20% of chronically infected patients will progress to cirrhosis after 20 or more years of infection. Therefore, it is likely that the majority of patients with hepatitis C infection will not progress to cirrhosis within their lifetimes. However, 15-25% of patients who acquired HCV infection under 45 years of age can spontaneously recover from their infections, and the proportion may be as high as 40-45% among patients who acquired their infections as children or young adults. These patients can be identified by the presence of multiple negative HCV RNA PCR tests with serologically positive anti-HCV antibody and previously confirmed infection.

What factors can accelerate hepatitis C progression?

Factors that can accelerate progression of liver disease in patients with hepatitis C infection include concurrent alcoholism, nonalcoholic fatty liver disease due to the metabolic syndrome, HIV co-infection, or chronic immunosuppression in transplant patients.

Should patients with chronic hepatitis C be routinely screened for hepatitis B? And if they are susceptible, should they be immunized against it?

All patients with chronic liver disease, including chronic hepatitis C, should be routinely screened for hepatitis B by checking hepatitis B surface antigen. If they are susceptible, which is documented by a negative antibody to hepatitis B surface antigen, then they should be vaccinated against hepatitis B.

What precautions should this patient take in reducing his risk of hepatitis C transmission?

Recommendations to avoid transmission of hepatitis C from the 1997 National Institutes of Health (NIH) Consensus Committee include adherence to universal healthcare precautions; no donation of blood, organs, tissues, or semen; use of condoms by individuals who have multiple sexual partners; avoiding the sharing razors and toothbrushes; and covering open wounds.³ However, no changes are recommended for sexual practices in monogamous long-term relationships, and there is no need to avoid close contact with family members or the sharing of meals and utensils.

Do alanine aminotransferase (ALT) levels and HCV RNA titers correlate with liver disease severity?

ALT levels and serum HCV RNA titers normally fluctuate during the course of hepatitis C infection. Therefore, they do not correlate with liver disease severity.

When would you recommend a liver biopsy?

Liver biopsy is indicated for staging of fibrosis in hepatitis C infection and is definitive for determining liver disease severity. In the absence of clinical signs or symptoms of advanced liver disease — which include hypoalbuminemia, thrombocytopenia, prolonged prothrombin time, palpable firm liver, vascular spiders or palmar erythema on physical exam, or imaging evidence of cirrhosis or portal hypertension &mdash; a staging liver biopsy is typically obtained to help determine which patients should be considered for antiviral therapy.

For patients with progressive hepatitis C infection and advanced fibrosis, antiviral therapy would be considered more urgent in order to hopefully slow disease progression, whereas in patients with no or minimal fibrosis, antiviral therapy could be avoided or postponed.

What is the treatment for chronic HCV infection?

The currently approved treatment for chronic hepatitis C infection is triple combination therapy with pegylated interferon + ribavirin + a protease inhibitor like telaprevir or boceprevir for 24 or 48 weeks for HCV genotype 1, or pegylated interferon + ribavirin for 24 weeks for HCV genotypes 2 and 3.

What factors predict response to antiviral treatment?

A sustained virological response (SVR) following antiviral therapy is considered to be permanent clearance of hepatitis C virus, or a “cure.” In HCV genotype 1 patients, SVR with triple therapy is approximately 65-75%, while in genotypes 2 and 3, SVR with combination therapy is approximately 75%. Factors predictive of SVR with interferon-based therapy include patients’ hepatitis C genotype, their on-treatment early virological response at week 4, and their IL28B genotype. Patients with IL28B genotype CC are the most responsive to interferon therapy, while those with genotype TT are the least responsive.

What are the contraindications to those agents?

Interferon therapy has considerable toxicity and can worsen underlying medical conditions, including decompensated cirrhosis, autoimmune disorders, psychiatric disorders, and hematologic disorders. Therefore, absolute contraindications to interferon therapy include decompensated cirrhosis, active alcohol or drug use, severe cytopenias or bone marrow diseases, severe or uncontrolled psychiatric disorders, uncontrolled autoimmune disorders, AIDS, advanced malignancies, and renal transplant patients. Relative contraindications to interferon-based therapy include patients with significant cardiopulmonary diseases, myelosuppressive disorders, brittle diabetes, and thyroid disorders, as well as those who are older than 65. Ribavirin in particular has known teratogenic effects and is absolutely contraindicated in pregnancy.

What are the drugs’ common side effects?

Common side effects of interferon therapy include flu-like symptoms at initiation, nausea, alopecia, somnolence, depression, neutropenia, thrombocytopenia, fatigue, myalgias, headache, fever, and arthralgias. Ribavirin’s side effects may include headache, fever, myalgias, fatigue, nausea with epigastric discomfort, and hemolytic anemia. Side effects of protease inhibitors telaprevir and boceprevir include fatigue, fever, nausea, diarrhea, significant anemia, dysgeusia, and severe rash and anorectal pain and itching with telaprevir.

The patient chooses not to undergo treatment for hepatitis C. What follow-up would be recommended?

The patient should be followed regularly in clinic, typically biannually. In the absence of known cirrhosis, regular monitoring of hepatic panel for hypoalbuminemia or hyperbilirubinemia, complete blood count for progressive thrombocytopenia, and regular physical examination for evidence of a firm liver edge, splenomegaly, or cutaneous signs of chronic liver disease should be sufficient to gauge for disease progression. In a patient with known cirrhosis, screening for hepatocellular carcinoma (HCC) is indicated. The patient should also be counseled regarding alcohol cessation. Additionally, aggressive management of metabolic syndrome via weight loss, diabetes control, or lipid control is indicated in patients with steatohepatitis due to the metabolic syndrome.

What is recommended in regard to HCC screening?

Regular screening for HCC is indicated in all patients with known cirrhosis from hepatitis C or any other etiology. Though screening for HCC is not necessary in the absence of cirrhosis, one exception to this rule is in patients with chronic hepatitis B, in whom HCC can develop without cirrhosis. Among patients with hepatitis B, screening for HCC is recommended starting at age 40 for men and age 50 for women, or at any age for those with a family history of liver cancer. Screening for HCC should include abdominal ultrasound scan and serum alpha-fetoprotein determinations every 6 months.

What does the future hold for better-tolerated, non-interferon-based therapies?

Clinical research on newer interferon-free treatments has been progressing very rapidly, and direct-acting antivirals (DAAs) targeting multiple hepatitis C structural and non-structural proteins and enzymes are currently under development. In clinical trials, combinations of DAAs targeting different viral proteins have shown considerable promise with excellent antiviral efficacy and considerably fewer side effects compared to current interferon-based regimens. It is expected that the first of these newer interferon-free regimens will be approved within the next year.

References

1. Moyer VA. Screening for hepatitis C virus infection in adults: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Sep 3;159(5):349-57. http://annals.org/article.aspx?articleid=1700383.

2. Alter MJ, Kuhnert WL, Finelli L. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. MMWR Recomm Rep. 2003 Feb 7;52(RR-3):1-13, 15. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5203a1.htm.

3. National Institutes of Health Consensus Development Conference Panel statement: Management of hepatitis C. Hepatology. 1997 Sep;26 (3 Suppl 1):2S-10S. http://onlinelibrary.wiley.com/store/10.1002/hep.510260701/asset/510260701_ftp.pdf?v=1&t=hopykv54&s=a65a8727fe5864f759e8f6579539d15656a20c07&systemMessage=Wiley+Online+Library+will+be+disrupted+on+7+December+from+10%3A00-15%3A00+BST+%2805%3A00-10%3A00+EDT%29+for+essential+maintenance.

About the Author

Steven-Huy Han, MD, is Clinical Professor of Medicine and Surgery at the David Geffen School of Medicine at UCLA. All questions were posed by Family Practice Recertification Editor-in-Chief Martin Quan, MD.