Affecting more than 3 million Americans, the hepatitis C virus (HCV) is the most common blood-borne pathogen producing a chronic infection within our country today.1,2 Since 1994, the prevalence of chronic HCV infections has been decreasing.3 However, as our chronically infected population ages, significant increases in morbidity, mortality, and health care costs will persist for many years to come.3
In 2012, to assist in the identification of undiagnosed infections, CDC expanded the one-time-screening recommendations to include individuals born between 1945 and 1965 (Table 1). Within this birth cohort, infections are five times more common than in the general population.4
Disease etiology and course
HCV is an RNA virus that primarily infects hepatocytes and leads to chronic inflammation of the liver.6 The virus is currently classified into six known genotypes (i.e., 1–6), which can be further subtyped.6 Genotype 1 is most common in the United States and typically the most challenging to treat.6
Patients who are acutely infected with HCV are generally asymptomatic and unaware of their infectious status. If symptoms do appear, they are typically nonspecific in nature (e.g., anorexia, dark urine, fatigue, jaundice).6 In some patients, the immune system will successfully clear the virus; however, in up to 85% of patients, the infection will progress to chronic hepatitis.7 Untreated infections can lead to cirrhosis of the liver, which may prompt further complications such as hepatocellular carcinoma.8 (Figure 1.) Chronic HCV infections are currently the leading indication for liver transplantations in the United States.8
Figure 1. Progression of HCV if left untreated
Source: Centers for Disease Control and Prevention. Hepatitis C information for health professionals. Available at www.cdc.gov/hepatitis/HCV/HCVfaq.htm. Accessed February 11, 2014.
Copyright © 2014, Diplomat Pharmacy Inc. All rights reserved. Reproduced with permission.
In addition to preventing further complications and disease transmission, the overall goal of HCV treatment is the attainment of a sustained virologic response (SVR), or “virologic cure.”6 Historically, SVR was defined as an undetectable viral load at 24 weeks after the completion of HCV therapy; however, recent outcome assessments have demonstrated the utility of SVR rates being measured at 12 weeks. Patients achieving SVRs have significant decreases in mortality risk.9
Following the discovery of HCV in the late 1980s, treatment strategies to combat this virus have emerged. Taking a quick glance at medical journals from the early 1990s easily makes one appreciate how much progress has been made in treating this disease. Treatment first began with the use of an interferon alfa product requiring injections three times per week.6 However, the probability of successful treatment with interferon alfa was relatively low, with SVR rates below 10%.6
Years later, two pegylated versions of interferon alfa were approved for use as monotherapy in treating chronic HCV infections, allowing patients to inject at a lesser frequency of once weekly. The use of ribavirin in combination with peginterferon significantly improved SVR rates; this combination was considered the standard of care for many years.6 In 2011, the approvals of boceprevir and telaprevir represented major advances in the treatment of chronic HCV. These two agents are classified as first-generation protease inhibitors and are approved to treat genotype 1 infections in combination with both peginterferon alfa and ribavirin. While these two therapies brought about significant improvements in SVR rates, they also contributed to increased rates of adverse events, drug interactions, dietary restrictions, and complicated treatment schedules.
Simeprevir and sofusbuvir. In the latter part of 2013, the FDA approved simeprevir and sofosbuvir for treatment of chronic HCV infections. These two agents offer more favorable dosing, efficacy, and adverse effect profiles and represent another significant accomplishment in HCV drug development.5 Practice guidelines developed by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) were released in January 2014. These guidelines note that regimens containing either boceprevir or telaprevir are inferior to the newer therapies and are no longer recommended, even though the drugs remain FDA-approved for treatment of chronic HCV.5 Regimens that include sofosbuvir or simeprevir are now recommended for patients who are treatment-naive or treatment-experienced.5
Simeprevir is an HCV NS3/4A protease inhibitor currently approved for use in combination with both peginterferon and ribavirin to treat patients with genotype 1 infection.10 This agent’s mechanism of action is identical to that of boceprevir and telaprevir; therefore, simeprevir should not be used in patients who have previously failed therapy with either of these two agents, as viral cross-resistance is expected.10 If simeprevir is to be used in boceprevir- or telaprevir-experienced patients, resistance testing should be performed to assure that simeprevir will be effective. Simeprevir is available as 150-mg capsules that should be taken with food once a day for 12 weeks.10 Peginterferon and ribavirin should be continued for an additional 12 or 36 weeks, depending on a patient’s previous treatment history and viral response to therapy.10 Patients with genotype 1a infections that contain the Q80K polymorphism should not be prescribed or administered simeprevir, as it appears to be much less effective in this subpopulation.10
Sofosbuvir is an HCV NS5B polymerase inhibitor currently approved to treat patients with genotype 1, 2, 3, or 4 infections.11 This therapy works through a different mechanism and therefore can be used in patients who have previously failed a protease-inhibitor–based regimen. Sofosbuvir should be used in combination with peginterferon and ribavirin for genotypes 1 and 4.11 For genotypes 2 and 3, it can be used with ribavirin alone.11 The duration of therapy is generally 12 or 24 weeks, depending on the genotype present.11 Sofosbuvir is also approved for use in patients coinfected with HIV as well as patients with hepatocellular carcinoma awaiting liver transplantation.11 This medication is available as 400-mg tablets and is recommended to be taken once daily with or without food.11
Investigational agents. Clearly, great changes have been occurring in the treatment of chronic HCV, and more than 20 other oral agents are being studied in Phase II and III trials; at least two new regimens for HCV are expected to be approved in 2014.12 In February, Gilead Sciences filed a new drug application for a combination regimen of ledipasvir and sofosbuvir for the treatment of genotype 1 infection.13 These two therapies are expected to be combined into one tablet that is taken once a day for either 8 or 12 weeks depending upon patient factors.13 Common adverse effects observed in studies reported to date include headache and fatigue.14 If approved, this regimen would not require the concomitant use of peginterferon and/or ribavirin. An FDA decision is expected in mid to late 2014.
A five-drug regimen sponsored by AbbVie is expected to be filed with the FDA sometime in the next few months. While this may seem like a high pill burden for the patient, three of these medications (ABT-450, ABT-267, ritonavir) are expected to be coformulated into a once-daily tablet.15 The other agents, ABT-333 and ribavirin, will be administered twice daily.15 Treatment duration, determined by patient-specific factors, is expected to be 12 or 24 weeks.15 Adverse effects observed in studies have been similar to those with ledipasvir/sofosbuvir regimens.15 Both of these regimens display very impressive efficacy data in treating HCV genotype 1 infections and will be important additions to available options.