The AASLD/IDSA Guideline for Treatment of Hepatitis C Virus: An In-Depth Guide

Of the 3 to 4 million Americans with chronic HCV infection, only 13% to 18% have received treatment. Understanding the current guidelines in HCV treatment and understanding the current role of direct-acting antiviral agents is an important priority for pharmacists.

With the availability of new agents in the rapidly changing field of hepatitis C virus (HCV), pharmacists are expected to understand the treatment options for HCV infection and discuss the importance of testing with at-risk patients. Currently in the United States, approximately half of the people estimated to have chronic HCV infection are aware that they even have the infection, while only 13% to 18% of all patients receive treatment.¹

HCV infection affects approximately 3 to 4 million Americans, about three-fourths of whom are members of the generation born between 1945 and 1965—baby boomers. Because approximately 3% of people in this age group are thought to have HCV infection, several medical societies —including the Centers for Disease Control, American Association for the Study of Liver Disease, Infectious Diseases Society of America, and United States Preventive Services Task Force—recommend universal 1-time testing for all patients born between 1945 and 1965.^1-3

Other populations for whom testing is recommended include¹:

• Anyone who has ever been incarcerated (approximately 29% of people who have ever been incarcerated are estimated to have anti-HCV antibodies)
• Patients who have ever used an illicit drug (including intranasal and intravenous drugs)
• Anyone who received a blood transfusion before July 1992
• Recipients of clotting factor concentrates manufactured prior to 1987
• Anyone who has received a tattoo in an unregulated setting
• Anyone who has undergone long-term hemodialysis (even if the person has had a kidney transplant and is no longer on hemodialysis)
• Health care workers after an accidental needle stick or other exposure to potentially infective fluids
• Anyone with HIV infection
• Anyone with unexplained elevations of liver enzyme levels
• Children of mothers with chronic HCV infection
• Other populations, as indicated by guidelines

Testing Specifics

Initial testing for HCV involves a test for the presence or absence of anti-HCV antibodies, followed by a test for the presence of HCV RNA copies. It is important to understand the meaning of the results for each of these tests¹:

• A patient with a positive test result for anti-HCV antibodies may have had an acute infection of HCV that resolved spontaneously (spontaneous resolution occurs in many cases of acute HCV infection, but even after resolution of an acute infection, anti-HCV antibodies remain in circulation)
• If a patient had a positive test result for anti-HCV antibodies, the next step is confirmatory testing for the presence or absence of copies of HCV RNA through polymerase chain reaction (PCR)
• Patients with suspected exposure to HCV in the 6 months prior to receiving a positive test result for anti-HCV antibodies should be tested using a special assay called a nucleic acid test. This test detects the presence or absence of active virus in the body

In patients with a positive test result for presence of HCV RNA through PCR testing, testing involves characterization of¹:

• The concentration of virus (in IU per mL)
• The virus genotype (HCV genotypes 1, 2, 3, 4, 5, and 6 exist, with additional subtypes denoted by letters, such as genotype 1a or 1b)

Treatment Efficacy

With hepatitis C, the efficacy of treatments are measured in terms of rates of sustained viral response. HCV RNA levels are assessed 12 to 24 weeks after the end of treatment. Patients who have undetectable levels of HCV RNA 12 to 24 weeks after the end of treatment are functionally cured, meaning that they have a 98% to 99% chance of remaining free of HCV infection indefinitely.⁴

Overview

By the late 2000s, the standard treatment of hepatitis C infection was peginterferon with ribavirin. In 2011, the FDA approved the protease inhibitors boceprevir and telaprevir for add-on treatment to peginterferon and ribavirin to boost rates of sustained viral response. As of 2014, most first-line treatment regimens still contain peginterferon and ribavirin, but telaprevir and boceprevir are no longer recommended, and have been replaced by newer agents known as direct-acting antivirals (DAAs). Currently approved DAAs are usually used with both peginterferon and ribavirin to treat eligible patients.^1,5,6

Sofosbuvir (Sovaldi), a DAA produced by Gilead Biosciences Inc, is an orally administered NS5B polymerase inhibitor. Patients who have not received prior treatment and have genotype 1, 2, 3, 4, 5, or 6 HCV infection are now generally treated with a sofosbuvir-based regimen as a first-line option.^1,7

Simeprevir (Olysio), a DAA produced by Bristol-Myers Squibb, is an orally administered NS3/4A protease inhibitor. A simeprevir-based regimen is an alternative option to a sofosbuvir-based regimen in patients with genotype-1 HCV infection. Although an indication has not yet been secured from the FDA for combination treatment with sofosbuvir, guidelines already recommend use of simeprevir and sofosbuvir in combination as a first-line regimen for patients with genotype-1 chronic HCV who have failed to achieve a cure with a prior round of therapy with interferon/ribavirin combination treatment.^1,8

Interferon and Ribavirin Eligibility

Not all patients are eligible for treatment with interferon. Patients who are ineligible include¹:

• Patients with any of the following blood test abnormalities: Hemoglobin levels <10 grams per deciliter Platelet counts <90,000 cells per microliter Neutrophil counts <1500 cells per microliter

• Cardiac disease or a history of cardiac disease
• Patients with certain liver problems, including autoimmune hepatitis or decompensated hepatic disease
• Patients with any autoimmune disorder
• Patients who cannot tolerate interferon treatment

Treatment-Naive Patients

In interferon-eligible patients, 12 weeks of combination treatment with sofosbuvir, peginterferon, and weight-based ribavirin (meaning 1000 mg daily for patients weighing <75 kg or 1200 mg daily for patients ≥75 kg) are recommended as first-line therapy in genotypes 1, 4, 5, and 6 HCV.¹

First-line treatment for genotype-2 and -3 HCV infection is sofosbuvir plus ribavirin in the absence of interferon because, in clinical trials, addition of interferon to the 2-drug regimen was associated with lower rates of sustained viral response. For patients with genotype-2 HCV, guideline authors recommend 12 weeks of treatment, while a longer, 24-week course of therapy is recommended in patients with genotype-3 HCV.¹

Treatment-Experienced Patients Who Have Not Achieved Cure With Prior Therapy

In patients who have failed to achieve sustained viral response with combination peginterferon/ribavirin treatment, first-line therapy for patients with genotype 4, 5, and 6 HCV infection includes sofosbuvir, peginterferon, and ribavirin for 12 weeks (or, optionally, for 24 weeks in genotype-4 HCV infection).¹

Peginterferon is eliminated from the regimen in treatment-experienced patients with genotype-2 or -3 HCV infection. For these patients, first-line therapy constitutes sofosbuvir plus ribavirin for 12 weeks (in genotype 2) or for 24 weeks (in genotype 3).

For patients with genotype-1 infection, the recommended first-line therapy is 12 weeks of therapy with sofosbuvir and simeprevir with or without ribavirin. The use of these agents together constitutes the first guideline-recommended first-line treatment for HCV that includes an option for an interferon-free and ribavirin-free regimen. Support for use of this regimen comes from an ongoing phase IIa clinical trial known by the acronym COSMOS. Results of the study are expected in early 2014 (see http://clinicaltrials.gov/ct2/show/study/NCT01466790 for more information).^1,9

HIV/HCV Coinfected Patients

Treatment recommendations for patients coinfected with HIV and genotype-4, -5, or -6 HCV infection are identical to recommendations for patients who are not coinfected with HIV. However, first-line treatment for patients with HIV who also have genotypes-1, -2, and -3 HCV diverges from first-line therapy in non—HIV-infected patients.¹

In genotype-2 and -3 infection, first-line treatment is a regimen of sofosbuvir and ribavirin for 12 weeks (in genotype-2 HCV infection) or 24 weeks (in genotype-3 HCV infection).¹

Physicians have more latitude in first-line options for treatment of patients with HIV who also have genotype-1 HCV infection. Two first-line options are available, but each option has a different level of evidence supporting the recommendation of its use¹:

• A high level of evidence (level I) supports use of: Sofosbuvir, peginterferon, and ribavirin for 12 weeks; or, for interferon-ineligible patients, sofosbuvir and ribavirin for 24 weeks

• A slightly lower level of evidence (level IIa) supports use of: Sofosbuvir plus simeprevir with or without ribavirin for 12 weeks

These recommendations, and the level of evidence associated with each recommendation, may change after publication of the final results of the COSMOS study.^1,9

Patients with Renal Impairment and Patients with Cirrhosis

Because sofosbuvir is not approved for patients with end-stage renal disease or in patients with a creatinine clearance <30 mL/min, the standard treatments remain peginterferon and ribavirin. Although patients with decompensated cirrhosis may receive up to 48 weeks of treatment with sofosbuvir and ribavirin, patients with decompensated cirrhosis should not receive treatment with interferon or peginterferon. Use of interferons in patients with decompensated cirrhosis may cause further liver damage.¹

Conclusion

Understanding the current place in therapy of direct-acting antiviral agents is an important role of pharmacists. Although many agents are in development, and wider use of both interferon-free and ribavirin-free regimens are expected in the near future, it is important to maintain a general understanding of the state of the art in treatment. Treatment guidelines in HCV are continually updated on the Web at HCVGuidelines.org.¹

References

• American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA). Recommendations for Testing, Managing, and Treating Hepatitis C. www.hcvguidelines.org/. Accessed March 13, 2014.
• United States Preventives Services Task Force (USPSTF). Screening for Hepatitis C Virus Infection in Adults. www.uspreventiveservicestaskforce.org/uspstf/uspshepc.htm. Accessed March 13, 2014.
• Centers for Disease Control (CDC). Hepatitis C: Why Baby Boomers Should Get Tested. www.cdc.gov/knowmorehepatitis/Media/PDFs/FactSheet-boomers.pdf. Accessed March 13, 2014.
• Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology. 2013;144(7):1450-1455.
• VICTRELIS (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2013.
• INCIVEK (telaprevir) tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2013
• OLYSIO (simeprevir) capsules [package insert]. Titusville NJ: Janssen Therapeutics; 2013.
• SOVALDI (sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences, Inc; 2013.
• ClinicalTrials.gov. A Study of TMC435 in Combination With PSI-7977 (GS7977) in Chronic Hepatitis C Genotype 1-Infected Prior Null Responders To Peginterferon/Ribavirin Therapy or HCV Treatment-Naive Patients (COSMOS). http://clinicaltrials.gov/ct2/show/NCT01466790. Accessed March 13, 2014.