DISEASE BURDEN
Hepatitis C is a blood-borne disease of the liver that is caused by infection with the hepatitis C virus (HCV), which can lead to serious liver problems such as cirrhosis and liver cancer. Approximately 4.1 million Americans (~1.6%) have evidence of HCV infection (1, 2) with about 20,000 new infections occurring annually (3). Approximately 75%-85% of infected persons are chronically infected, placing them at risk for hepatocellular carcinoma (HCC), cirrhosis, and extrahepatic complications that develop after decades of untreated infection (4). Data from 1999 to 2007 indicates that deaths from HCV have increased significantly, whereas those linked to hepatitis B (HBV) remained constant and HIV-associated mortality decreased (5).

 

The majority of people with chronic HCV are unaware of their infection because the disease remains asymptomatic until the advanced stages. According to the CDC, of every 100 persons infected with HCV, approximately 75-85 will go on to develop chronic infection, 60-70 will go on to develop chronic liver disease, 5-20 will go on to develop cirrhosis over a period of 20-30 years, and 1-5 will die from the consequences of chronic infection (liver cancer or cirrhosis) (4). HCV-associated, end-stage liver disease is the leading indication for liver transplantation in adults and a leading cause of HCC in the United States (6).

 

In the United States, HCV infection is most prevalent among adults born from 1945 through 1965 (4), and this birth-cohort accounts for about 73% of HCV-associated mortality (5). Since more than 50% of infected adults are unaware of their infections, the number of patients with chronic HCV C that will progress to cirrhosis, liver failure, HCC, and death is expected to increase dramatically in the coming decades (7,8). Without changes to HCV diagnosis and treatment paradigms, total medical costs for patients with HCV infection are expected to more than double from $30 billion to over $85 billion over the next 20 years (9).

 

Major advances in the treatment of HCV have been made in the last decade and additional treatments are on the horizon. However, previous risk-based screening strategies have met limited success as evidenced by the substantial number of HCV-infected persons who remain unaware of their infection. In recent years, screening and linkage to care recommendations for HCV have been modified in order to identify unrecognized infections and link infected patients into appropriate care. Following these recommendations will reduce the onset of severe HCV-related disease.

 

TRANSMISSION AND RISK FACTORS
The HCV virus is transmitted through percutaneous exposure to infected blood. Common routes of infection include injection drug use, receipt of donated blood or blood products (before 1992), needlestick injuries in healthcare settings, and any other exposure to contaminated blood from an infected person (e.g. birth to an HCV-infected mother).

 

Approximately 20%-30% of those newly infected with HCV experience fatigue, abdominal pain, poor appetite, or jaundice. The average time period from exposure to symptom onset is 4-12 weeks (range: 2-24 weeks) (10). However, patients with newly acquired infections often do not visit a health care professional because many are asymptomatic or experience only flu-like symptoms. Since regular examinations most often do not involve routine HCV screenings, HCV infection is often only identified through blood donation screenings.

 

IMPORTANCE OF TESTING AND LINKING TO CARE
Over 4 million people are living with chronic HCV infection while only 100,000 are both aware of their infection and receive treatment (6). In one study looking at 3.3 million patients in the United States with HCV infection, as many as 2.5 million were unaware of their status (11). Reasons for failure to identify patients with chronic HCV include: (a) asymptomatic patients without any other medical problems may not seek medical attention, (b) many primary care physicians lack knowledge about HCV risk factors and testing, (c) patients may be reluctant to reveal risk factors, and (d) patients may be outside healthcare system (young, poor, drug addicts). HCV testing followed by appropriate linkage to care is a critical first step toward improving health outcomes for persons infected with HCV.

 

There are clear health risks to delaying treatment. HCV can stay active in the body and attack the liver for years without producing recognizable symptoms. According to the CDC, of every 100 persons infected with HCV, approximately 50-80% will go on to develop chronic infection. After 20 to 30 years of untreated chronic infection, approximately 20-30% of these individuals will have evidence of cirrhosis. Once cirrhosis occurs, decompensation can develop at a rate of 6-10% per year. Decompensation in this patient population is defined as encephalopathy, ascites, variceal bleeding, and/or spontaneous bacterial peritonitis. These patients are also at risk for developing hepatocellular carcinoma (HCC). Patients with decompensated cirrhosis and/or HCC likely require liver transplantation (12,13,14).

 

WHO SHOULD BE TESTED FOR HCV
Based on the data described above, the CDC has augmented previous recommendations for HCV testing. It is now recommended that persons born during 1945-1965 undergo one-time HCV testing without prior ascertainment of HCV risk. In addition, the Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA), have developed evidence-based, expert-developed recommendations for HCV management, which include recommendations on HCV testing and linkage to care. This "living document" echoes the CDC's recommendation for one-time birth cohort HCV testing. These guidelines also recommend that other persons should be screened for risk factors for HCV infection, and one-time testing should be performed for all persons with behaviors, exposures, and conditions associated with an increased risk of HCV infection. Below are additional details from the guidelines(15):

 

  • HCV testing is recommended at least once for persons born between 1945 and 1965.
  • Other persons should be screened for risk factors for HCV infection, and one-time testing should be performed for all persons with behaviors, exposures, and conditions associated with an increased risk of HCV infection.
    • Risk behaviors
      • Injection-drug use (current or ever, including those who injected once)
      • Intranasal illicit drug use
    • Risk exposures
      • Long-term hemodialysis (ever)
      • Getting a tattoo in an unregulated setting
      • Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-infected blood.
      • Children born to HCV-infected women
      • Prior recipients of transfusions or organ transplants, including persons who:
        • were notified that they received blood from a donor who later tested positive for HCV infection
        • received a transfusion of blood or blood components, or underwent an organ transplant before July 1992
        • received clotting factor concentrates produced before 1987
      • Persons who were ever incarcerated
    • Other medical conditions
      • HIV infection
      • Unexplained chronic liver disease and chronic hepatitis including elevated alanine aminotransferase levels

 

Furthermore, persons who inject drugs and HIV-seropositive men who have unprotected sex with men should undergo annual HCV testing. Finally, periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV (15).

 

TESTING FOR HCV
Several blood tests are performed to test for HCV infection. The first screening test detects the presence of antibodies to HCV (anti-HCV) to evaluate exposure to the HCV virus. A second confirmatory test is usually recommended to provide serologic evidence of HCV infection (HCV RNA) using a recombinant immunoblot assay (RIBA) or nucleic acid test (qualitative detection of HCV RNA (PCR).

 

Several anti-HCV antibody screening test kits have been licensed or approved by the FDA for use in the United States. Examples include: two enzyme immunoassays (EIA) - (Abbott HCV EIA 2.0, Abbott Laboratories, Abbott Park, Illinois; and ORTHO® HCV Version 3.0 ELISA, Ortho-Clinical Diagnostics, Raritan, New Jersey) and one enhanced chemiluminescence immunoassay (CIA) (VITROS® Anti-HCV assay, Ortho-Clinical Diagnostics, Raritan, New Jersey).

 

In 2010, the FDA approved the use of OraQuick(R) Hepatitis C ("HCV") Rapid Antibody Test for detecting HCV antibodies in venous whole blood specimens, making it the first rapid HCV test approved by the FDA for use in the United States. More recently, the FDA has granted a waiver under the Clinical Laboratory Improvement Amendments of 1988 ("CLIA") for the OraQuick® HCV Rapid Antibody Test for use with fingerstick whole blood and venous whole blood specimens. With this waiver, the OraQuick® HCV test now can be used by more than 180,000 sites in the United States to test persons who are at risk for hepatitis C or have signs or symptoms of hepatitis. These sites now extend to facilities that can perform CLIA-waived tests, such as outreach clinics, community-based organizations and physician offices. The test, which utilizes the OraQuick® technology platform, provides results in 20 minutes (16).

 

TREATMENT OPTIONS
The first step in the management of HCV is appropriate linkage to care, or evaluation by a practitioner who is prepared to provide comprehensive management. Treatment is recommended for patients with chronic HCV infection in order to reduce all-cause mortality and liver-related health adverse consequences. The goal of treatment is to achieve a sustained viral response (SVR), defined as the continued absence of detectable HCV RNA at least 12 weeks after completion of therapy (15). SVR is a marker for cure of HCV infection.

 

Until recently, the standard of care for the treatment of HCV was the combination of pegylated interferon and ribavirin. This regimen involves patient subcutaneous self-injections of pegylated interferon and has limited efficacy and poor tolerability. Clinicians now have more sophisticated antiviral therapies to choose from that have dramatically improved the management of HCV. New HCV treatment options, known collectively as direct acting antivirals (DAAs) have moved toward those with oral delivery, shorter durations, improved efficacy and minimal side effects.

 

In 2013, two second generation DAA's were FDA approved and are already demonstrating additional benefits in patients with HCV. Simeprevir is an oral NS3/4A protease inhibitor for the treatment of HCV genotype 1 (in combination with pegylated interferon and ribavirin). In clinical trials, 80% of genotype 1 patients administered simeprevir achieved SVR12 (17). Sofosbuvir is an oral nucleotide analog NS5B polymerase inhibitor for the treatment of chronic genotype 1, 2, 3 and 4 HCV. The combination of sofosbuvir, pegylated interferon and ribavirin has demonstrated SVR12 rates of 90% in genotype 1 patients (18).

 

In 2014, an additional second generation DAA was added to the HCV treatment armamentarium. Ledispravir is an HCV NS5A inhibitor and is available only in combination with sofosbuvir. This combination is the first once-daily single tablet oral regimen for the treatment of chronic hepatitis C genotype 1 infection in adults. In clinical trials, SVR12 reached as high as 99% in patients administered the ledispravir/sofosbuvir combination pill alone (19).