Breakthrough is an overused term in science and medicine. However, there is no doubt it is an appropriate description for the historic advances in diagnosing and treating the hepatitis C virus (HCV) that have been made over the last few decades.
New treatments and new challenges
That hepatitis C is a rapidly evolving landscape is demonstrated by the rapid emergence of new drug treatments and diagnostic tests. Highly potent new drugs have been shown to cure HCV infections in the vast majority of patients, with shorter treatment course and significantly lower side effects than previous grueling treatments containing antiviral agents such as interferon. The traditional interferon-ribaviron antiviral regimen is about 50% effective in curing HCV, while adding a new medication increases the cure rate to as high as 95%. Millions of Americans potentially harbor the infection, and now treatment that features decreased side effects and high cure rates is available to them. Accurate and early diagnosis of people with HCV is of crucial importance, in terms of lives to be saved, healthcare costs to be reduced, and an epidemic to be curbed.
In the United States, 2.7 to 3.9 million individuals are living with HCV, according to the U.S. Centers for Disease Control and Prevention (CDC), and of these individuals 15,000 die every year.1 Approximately 85% of those infected with HCV have chronic disease, and most are unaware of it. The CDC estimates that for individuals born between 1945 and 1965, the prevalence of HCV infection is five times higher than among other age groups, and that this group represents 73% of all HCV-associated mortality.1 Because of this increased risk of infection and disease prevention, the CDC is actively encouraging baby boomers to be tested for HCV and seek treatment to help prevent chronic liver disease, cancer, or other downstream complications.
Increased testing for HCV will fuel greater demand for new direct-acting antiviral drug treatments (simiprevir, sofosbuvir), but the most widely used new agent, sofosbuvir, costs roughly $90,000 for three months of treatment.
The potential costs associated with treating every HCV-infected person in the United States at these prices have received significant attention from the media and the U.S. Congress. Final data from the Phase 2 COSMOS study presented at the 2014 International Liver Congress showed that 93% of patients with HCV genotype 1 and advanced liver fibrosis who were treated with both sofosbuvir and simeprivir for 12 weeks without interferon were effectively cured. (That is, HCV RNA was not detected in the blood 12 weeks after therapy).2 The study’s impressive results are noteworthy but come at a cost of $180,000 for 12 weeks of therapy. The prices of these breakthrough regimens, however, are justified by cost savings in subsequent treatment for liver disease, including liver transplant.
These treatment costs spotlight the importance of making sure the right patients are treated with the right new therapies, at the right time. While new HCV drugs have captured headlines, notable advances in hepatitis diagnostics also have occurred, especially in hepatitis genotype testing. New HCV therapies have indications for specific HCV genotypes, which include duration and drug combinations appropriate for use in a particular patient. Knowing the patient’s HCV viral genotype aids physicians in more precisely customizing anti-viral therapy. HCV genotype testing can now be performed in most clinical and hospital laboratories.
Once a patient is on treatment, the most direct measure of therapy effectiveness and patient adherence to these costly regimens remains the measurement of HCV RNA in the patient’s blood. An RNA test enables physicians to quantify the amount of replicating virus in the body. Understanding how fast these values decline after treatment is initiated has been very useful in predicting treatment success and guiding on-treatment clinical decisions. This test is important for physicians who are writing prescriptions, to health insurers who can be assured that the drug therapy is working as expected, and, equally important, as positive reinforcement for patients to keep faithfully taking their medication.
HCV genotype testing and targeted therapy
The hepatitis C virus is divided into six distinct genotypes, and each genotype has multiple subtypes. HCV is highly variable genetically, and the six major genotypes share 70% to 80% nucleotide identity with one another, along with more than 80 subtypes, which share 80% to 90% nucleotide identities within these genotypes. HCV genotype 1 accounts for about 60% of infections worldwide, and subtype 1a is the most common cause of infection in the United States.
Even though genotypes 1a and 1b are predominant in the United States, clinicians should not assume that each HCV infection encountered is genotype 1. Ethnic diversity within the nation and frequent international travel have increased the likelihood that other HCV genotypes could be present. An American who contracts HCV in India, for example, could have genotype 3, or an infection contracted in Egypt could be genotype 4.
Even within genotype 1, patients with subtype 1a infections have experienced a higher rate of drug resistance and viral breakthrough than subtype 1b. Studies identified that HCV subtype 1a naturally harbors one of the two mutations associated with the development of drug resistance to new protease inhibitors at a significantly higher frequency than subtype 1b.3 This implies that HCV subtype 1b has a higher barrier to antiviral drug resistance in this class of drug than subtype 1a. Finally, investigators have linked certain HCV genotypes to more rapid disease progression.
Personalizing primary care
The availability of highly effective new HCV drugs and better awareness among baby boomers about getting tested for HCV could increase testing volumes and identify thousands of new patients. This might exceed the capacity of liver specialists and even infectious disease physicians to keep up with demand. Fortunately, due to the short treatment duration and drug low side effect profile offered by these new regimens, treatment of hepatitis C may become more common in primary-care practices. Laboratories will need to take an aggressive role in educating physicians on proper diagnostic protocols for their HCV patients. This will assure optimal clinical outcomes and avoid improper prescribing of expensive drugs.
The logical first step is to find those who are infected. The CDC’s ongoing HCV awareness program, coupled with more aggressive outreach by public health organizations, is expected to motivate larger numbers of baby boomers and other high-risk groups, such as intravenous drug users and persons who practice unsafe, non-monogamous sex, to get tested.
A positive result on an HCV antibody test will alert a physician that a patient has been exposed to the HCV virus. Exposure could result in a short acute infection, which is spontaneously resolved by the body’s immune system, or chronic infection, persisting for years or even decades. Most HCV cases are chronic infections. A physician must determine if a patient with an HCV antibody-positive result has an active infection, and can confirm this by requesting tests that identify active replication through the presence of viral particles or their components in the blood. The detection of HCV RNA is recommended in treatment guidelines to confirm the presence of active infection. An alternative test, which can be used as an adjunct to confirm infection, detects a component of the HCV viral particle, core protein (antigen), and is known as the HCV antigen assay. This test is only available outside the U.S.
Considering the extremely high costs associated with treating patients with HCV infection, it is prudent for healthcare systems, insurers, and physicians to make the investment in diagnostic tests that can appropriately personalize their patients’ care and maximize the number cured of this potentially deadly disease.
- U.S. Centers for Disease Control and Prevention, CDC. Hepatitis C Information for the Public. www.cdc.gov. Accessed July 30, 2014.
- Johnson & Johnson, Final Data forum the Phase 2 COSMOS Study of Janssen’s Once-Daily Simiprevir in Combination with Sofosbuvir Presented. The International Liver Congress 2014 of the European Association for the Study of the Liver: April 12, 2014. www.jnj.com. Accessed July 30, 2014.
- Kuiken C, Simmonds P. Nomenclature and numbering of the hepatitis C virus. Methods MolBiol. 2009;510:33-53.