WHAT’S NEW IN INFECTIOUS DISEASE
New medications for treatment of chronic hepatitis C Melissa Murfin, PA-C, PharmD, BCACP
ABSTRACT Treating chronic hepatitis C is crucial to preventing longterm complications such as cirrhosis and liver cancer. New treatments may improve response rates, but the high cost of therapy is a major concern. This article reviews two of these new treatments, sofosbuvir and simeprevir. Keywords: chronic hepatitis C, genotype 1, simeprevir, sofosbuvir, protease inhibitors, treatment cost
Key points Sofosbuvir offers a significant improvement in sustained virologic response rates compared with current standard therapy for hepatitis C. Using sofosbuvir or simeprevir decreases length of therapy for hepatitis C and causes fewer adverse reactions. Sofosbuvir can be used to treat hepatitis C genotypes 1 through 4 but simeprevir is only indicated for genotype 1. Cost of both sofosbuvir and simeprevir may place these treatments out of reach of many patients. Patient assistance programs are available from each drug manufacturer.
C
hronic hepatitis C affects about 3 million people in the United States, and about half of those affected are undiagnosed.1 Without treatment, up to 70% of patients progress to liver disease, and up to 5% die of cirrhosis or liver cancer.2 Standard therapy is aimed at viral clearance, which prevents long-term complications, but involves several weeks of medications that cause significant adverse reactions. New medications offer the potential for greater response rates, a significantly shorter course of treatment, and fewer adverse reactions.
Melissa Murfin is an assistant professor in the PA program at Elon (N.C.) University. The author has disclosed no potential conflicts of interest, financial or otherwise. Mark E. Archambault, DHSc, PA-C, department editor DOI: 10.1097/01.JAA.0000466592.48713.85 Copyright © 2015 American Academy of Physician Assistants
TRADITIONAL TREATMENT Hepatitis C virus is subdivided into six genotypes that respond differently to treatment. Genotype 1, which accounts for 75% of cases in the United States, has the lowest response to treatment.3 The remaining cases are predominantly genotypes 2 and 3; fewer than 5% of cases are attributed to genotypes 4 through 6.3 A sustained virologic response at 24 weeks after treatment stops, or essentially an undetectable viral load, is considered a cure. This viral clearance reduces the patient’s risk for liver cancer and death.4 For more than 10 years, combination pegylated interferon and ribavirin were the standard of care for hepatitis C. Depending on patient response to therapy, about 40% of patients with genotype 1 who were treated with this regimen for up to 48 weeks achieved a cure.5 Patients with genotypes 2 or 3 who had 24 weeks of treatment had better response rates of up to 75%.5 However, this regimen is difficult for patients because it causes significant adverse reactions, including flu-like reactions with each weekly injection of peginterferon, blood dyscrasias, vision problems, and psychiatric issues including anxiety, depression, and insomnia.5 Ribavirin is associated with hemolytic anemia, and is not recommended for use in pregnant women or men with a pregnant partner because of the risk for fetal malformation.5 NEW DIRECT-ACTING ANTIVIRALS The first direct-acting antiviral (DAA) hepatitis C protease inhibitors were approved in 2011.1 These drugs, telaprevir and boceprevir, were the first new drugs for treatment of hepatitis C virus since pegylated interferon was approved in 2001.1 Telaprevir and boceprevir improved sustained virologic response, but both drugs are given in combination with pegylated interferon and ribavirin and require several pills given multiple times daily. Because new medications have been approved, telaprevir and boceprevir are no longer recommended for treating hepatitis C.1 Two additional DAAs for hepatitis C were approved in 2013. Simeprevir is a hepatitis C protease inhibitor and sofosbuvir is a hepatitis C RNA polymerase inhibitor. Both promise to increase sustained virologic response while shortening the course of treatment compared with the standard regimen of interferon and ribavirin. Simeprevir This drug was initially approved as triple therapy with interferon and ribavirin to treat chronic
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2015 American Academy of Physician Assistants
www.JAAPA.com
57
WHAT’S NEW IN INFECTIOUS DISEASE
TABLE 1. 2015 AASLD recommended initial treatment with sofosbuvir and simeprevir for treatment-naive patients with hepatitis C1
Genotype
First-line medication regimen
Alternate medication regimen
1, 4
Sofosbuvir and ledipasvir for 12 weeks
Sofosbuvir and simeprevir (with or without ribavirin) for 12 to 24 weeks depending on cirrhosis status
2
Sofosbuvir and ribavirin for 12 to 16 weeks depending on cirrhosis status
3
Sofosbuvir and ribavirin for 24 weeks
Sofosbuvir, ribavirin, and peginterferon for 12 weeks
5
Sofosbuvir, ribavirin, and peginterferon for 12 weeks
Peginterferon and ribavirin for 48 weeks
6
Sofosbuvir and ledipasvir for 12 weeks
Sofosbuvir, ribavirin, and peginterferon for 12 weeks
hepatitis C caused by genotype 1.6 However, the most recent guidelines from the American Association for the Study of Liver Diseases (AASLD) recommends using simeprevir with sofosbuvir and ribavirin for 12 weeks in patients who do not have cirrhosis; 24 weeks of treatment is recommended for patients with cirrhosis.1 Overall sustained virologic response for simeprevir triple therapy in treatment-naive patients with genotype 1 was 79% to 100%, a significant improvement compared with 50% for interferon and ribavirin.1,6 Some genetic variation in response to treatment with simeprevir is known. Patients with genotype 1a require a genetic test for a specific mutation known as Q80K. If the screening test is positive, simeprevir is not a treatment option due to decreased efficacy.6 Adverse reactions to simeprevir include rash, photosensitivity, pruritus, nausea, myalgia, and dyspnea.6 Simeprevir is metabolized by P450 enzymes in the liver and can interact with common medications such as macrolide antibiotics, statins, azole antifungals, and antiarrhythmics.6 Prescribers should be aware of this possibility when ordering other medications for patients taking simeprevir. Though simeprevir offers some potential improvement in cure for patients with genotype 1, the drug lacks efficacy in patients infected with other hepatitis C genotypes. Sofosbuvir This new once-daily oral DAA has a broader spectrum of action with shorter overall treatment in most cases. Sofosbuvir is the first HCV RNA polymerase inhibitor.7 A prodrug, it blocks viral reproduction in much the same way nucleoside/nucleotide reverse transcriptase inhibitors block viral reproduction in HIV. The prodrug is converted in the liver to an active antiviral drug and is further metabolized to an inactive metabolite.7 Drugs that induce metabolic enzymes, such as rifampin, carbamazepine, and St. John’s wort, may increase production of the inactive metabolite, reducing the efficacy of sofosbuvir.7 58
Sofosbuvir has activity against hepatitis C genotypes 1 through 4 and can be used in patients with liver cancer and concomitant HIV infection.7 Several clinical trials evaluated efficacy and tolerability in terms of SVR for each genotype. When used in previously untreated patients along with the standard treatment of interferon and ribavirin, 90% of patients with genotype 1 and 96% of patients with genotype 4 had a sustained virologic response after only 12 weeks of treatment.7 Between 82% and 95% of patients with genotype 2 had a sustained virologic response after 12 weeks of sofosbuvir with ribavirin alone.6 However, patients with genotype 3 did not fare quite as well: after 12 weeks of sofosbuvir and ribavirin, only 56% had a sustained virologic response.6 However, the percentage improved to 84% after 24 weeks of treatment.6 In comparison, 66% of patients with genotype 3 had a sustained virologic response after 24 weeks of standard treatment with peginterferon and ribavirin.8 Sofosbuvir is now approved for treating hepatitis C genotype 1 when used in a combination product with ledipasvir, a hepatitis viral replication inhibitor. This combination is considered first-line treatment for hepatitis C genotype 1.1 Sofosbuvir causes fewer adverse reactions than interferon, which improves tolerability for patients treated with sofosbuvir and ribavirin alone. The most common adverse reactions are nausea, fatigue, pain, hypertension, insomnia, and anxiety.7 Current joint treatment guidelines from the AASLD and the Infectious Diseases Society of America (IDSA) are summarized in Table 1. These recommendations eliminate peginterferon for treatment of patients with genotypes 2 and 3, greatly decreasing potential adverse reactions associated with its use. CONTROVERSY OVER COST Although the viral response numbers seem to indicate a huge breakthrough in treatment of hepatitis C, another set
www.JAAPA.com
Volume 28 • Number 7 • July 2015
Copyright © 2015 American Academy of Physician Assistants
New medications for treatment of chronic hepatitis C
Statistically significant sustained virologic response with sofosbuvir and simeprevir for hepatitis C treatment8,11-14
TABLE 2.
Regimen
Genotype
Length of treatment (weeks)
Overall sustained virologic response
Approximate total cost of treatment
Peginterferon and ribavirin
1-6
24-48
42%a-62%b
$36,000
Sofosbuvir and ledipasvir
1, 4
12
99%c
$94,000
Sofosbuvir and ribavirin
2
12
95%d
$86,500
Sofosbuvir and ribavirin
3
24
84%e
$173,000
Simeprevir, peginterferon, and ribavirin
1
12
80%f
$100,000
a
comparing higher-dose peginterferon plus ribavirin with standard interferon with ribavirin (P=0.02).11 comparing weight-based ribavirin with peginterferon to flat-dose ribavirin with peginterferon for treatment of genotypes 2 and 3 (P=0.252)8 c compared with adjusted historical response rate (P
New medications for treatment of chronic hepatitis C Melissa Murfin, PA-C, PharmD, BCACP
ABSTRACT Treating chronic hepatitis C is crucial to preventing longterm complications such as cirrhosis and liver cancer. New treatments may improve response rates, but the high cost of therapy is a major concern. This article reviews two of these new treatments, sofosbuvir and simeprevir. Keywords: chronic hepatitis C, genotype 1, simeprevir, sofosbuvir, protease inhibitors, treatment cost
Key points Sofosbuvir offers a significant improvement in sustained virologic response rates compared with current standard therapy for hepatitis C. Using sofosbuvir or simeprevir decreases length of therapy for hepatitis C and causes fewer adverse reactions. Sofosbuvir can be used to treat hepatitis C genotypes 1 through 4 but simeprevir is only indicated for genotype 1. Cost of both sofosbuvir and simeprevir may place these treatments out of reach of many patients. Patient assistance programs are available from each drug manufacturer.
C
hronic hepatitis C affects about 3 million people in the United States, and about half of those affected are undiagnosed.1 Without treatment, up to 70% of patients progress to liver disease, and up to 5% die of cirrhosis or liver cancer.2 Standard therapy is aimed at viral clearance, which prevents long-term complications, but involves several weeks of medications that cause significant adverse reactions. New medications offer the potential for greater response rates, a significantly shorter course of treatment, and fewer adverse reactions.
Melissa Murfin is an assistant professor in the PA program at Elon (N.C.) University. The author has disclosed no potential conflicts of interest, financial or otherwise. Mark E. Archambault, DHSc, PA-C, department editor DOI: 10.1097/01.JAA.0000466592.48713.85 Copyright © 2015 American Academy of Physician Assistants
TRADITIONAL TREATMENT Hepatitis C virus is subdivided into six genotypes that respond differently to treatment. Genotype 1, which accounts for 75% of cases in the United States, has the lowest response to treatment.3 The remaining cases are predominantly genotypes 2 and 3; fewer than 5% of cases are attributed to genotypes 4 through 6.3 A sustained virologic response at 24 weeks after treatment stops, or essentially an undetectable viral load, is considered a cure. This viral clearance reduces the patient’s risk for liver cancer and death.4 For more than 10 years, combination pegylated interferon and ribavirin were the standard of care for hepatitis C. Depending on patient response to therapy, about 40% of patients with genotype 1 who were treated with this regimen for up to 48 weeks achieved a cure.5 Patients with genotypes 2 or 3 who had 24 weeks of treatment had better response rates of up to 75%.5 However, this regimen is difficult for patients because it causes significant adverse reactions, including flu-like reactions with each weekly injection of peginterferon, blood dyscrasias, vision problems, and psychiatric issues including anxiety, depression, and insomnia.5 Ribavirin is associated with hemolytic anemia, and is not recommended for use in pregnant women or men with a pregnant partner because of the risk for fetal malformation.5 NEW DIRECT-ACTING ANTIVIRALS The first direct-acting antiviral (DAA) hepatitis C protease inhibitors were approved in 2011.1 These drugs, telaprevir and boceprevir, were the first new drugs for treatment of hepatitis C virus since pegylated interferon was approved in 2001.1 Telaprevir and boceprevir improved sustained virologic response, but both drugs are given in combination with pegylated interferon and ribavirin and require several pills given multiple times daily. Because new medications have been approved, telaprevir and boceprevir are no longer recommended for treating hepatitis C.1 Two additional DAAs for hepatitis C were approved in 2013. Simeprevir is a hepatitis C protease inhibitor and sofosbuvir is a hepatitis C RNA polymerase inhibitor. Both promise to increase sustained virologic response while shortening the course of treatment compared with the standard regimen of interferon and ribavirin. Simeprevir This drug was initially approved as triple therapy with interferon and ribavirin to treat chronic
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2015 American Academy of Physician Assistants
www.JAAPA.com
57
WHAT’S NEW IN INFECTIOUS DISEASE
TABLE 1. 2015 AASLD recommended initial treatment with sofosbuvir and simeprevir for treatment-naive patients with hepatitis C1
Genotype
First-line medication regimen
Alternate medication regimen
1, 4
Sofosbuvir and ledipasvir for 12 weeks
Sofosbuvir and simeprevir (with or without ribavirin) for 12 to 24 weeks depending on cirrhosis status
2
Sofosbuvir and ribavirin for 12 to 16 weeks depending on cirrhosis status
3
Sofosbuvir and ribavirin for 24 weeks
Sofosbuvir, ribavirin, and peginterferon for 12 weeks
5
Sofosbuvir, ribavirin, and peginterferon for 12 weeks
Peginterferon and ribavirin for 48 weeks
6
Sofosbuvir and ledipasvir for 12 weeks
Sofosbuvir, ribavirin, and peginterferon for 12 weeks
hepatitis C caused by genotype 1.6 However, the most recent guidelines from the American Association for the Study of Liver Diseases (AASLD) recommends using simeprevir with sofosbuvir and ribavirin for 12 weeks in patients who do not have cirrhosis; 24 weeks of treatment is recommended for patients with cirrhosis.1 Overall sustained virologic response for simeprevir triple therapy in treatment-naive patients with genotype 1 was 79% to 100%, a significant improvement compared with 50% for interferon and ribavirin.1,6 Some genetic variation in response to treatment with simeprevir is known. Patients with genotype 1a require a genetic test for a specific mutation known as Q80K. If the screening test is positive, simeprevir is not a treatment option due to decreased efficacy.6 Adverse reactions to simeprevir include rash, photosensitivity, pruritus, nausea, myalgia, and dyspnea.6 Simeprevir is metabolized by P450 enzymes in the liver and can interact with common medications such as macrolide antibiotics, statins, azole antifungals, and antiarrhythmics.6 Prescribers should be aware of this possibility when ordering other medications for patients taking simeprevir. Though simeprevir offers some potential improvement in cure for patients with genotype 1, the drug lacks efficacy in patients infected with other hepatitis C genotypes. Sofosbuvir This new once-daily oral DAA has a broader spectrum of action with shorter overall treatment in most cases. Sofosbuvir is the first HCV RNA polymerase inhibitor.7 A prodrug, it blocks viral reproduction in much the same way nucleoside/nucleotide reverse transcriptase inhibitors block viral reproduction in HIV. The prodrug is converted in the liver to an active antiviral drug and is further metabolized to an inactive metabolite.7 Drugs that induce metabolic enzymes, such as rifampin, carbamazepine, and St. John’s wort, may increase production of the inactive metabolite, reducing the efficacy of sofosbuvir.7 58
Sofosbuvir has activity against hepatitis C genotypes 1 through 4 and can be used in patients with liver cancer and concomitant HIV infection.7 Several clinical trials evaluated efficacy and tolerability in terms of SVR for each genotype. When used in previously untreated patients along with the standard treatment of interferon and ribavirin, 90% of patients with genotype 1 and 96% of patients with genotype 4 had a sustained virologic response after only 12 weeks of treatment.7 Between 82% and 95% of patients with genotype 2 had a sustained virologic response after 12 weeks of sofosbuvir with ribavirin alone.6 However, patients with genotype 3 did not fare quite as well: after 12 weeks of sofosbuvir and ribavirin, only 56% had a sustained virologic response.6 However, the percentage improved to 84% after 24 weeks of treatment.6 In comparison, 66% of patients with genotype 3 had a sustained virologic response after 24 weeks of standard treatment with peginterferon and ribavirin.8 Sofosbuvir is now approved for treating hepatitis C genotype 1 when used in a combination product with ledipasvir, a hepatitis viral replication inhibitor. This combination is considered first-line treatment for hepatitis C genotype 1.1 Sofosbuvir causes fewer adverse reactions than interferon, which improves tolerability for patients treated with sofosbuvir and ribavirin alone. The most common adverse reactions are nausea, fatigue, pain, hypertension, insomnia, and anxiety.7 Current joint treatment guidelines from the AASLD and the Infectious Diseases Society of America (IDSA) are summarized in Table 1. These recommendations eliminate peginterferon for treatment of patients with genotypes 2 and 3, greatly decreasing potential adverse reactions associated with its use. CONTROVERSY OVER COST Although the viral response numbers seem to indicate a huge breakthrough in treatment of hepatitis C, another set
www.JAAPA.com
Volume 28 • Number 7 • July 2015
Copyright © 2015 American Academy of Physician Assistants
New medications for treatment of chronic hepatitis C
Statistically significant sustained virologic response with sofosbuvir and simeprevir for hepatitis C treatment8,11-14
TABLE 2.
Regimen
Genotype
Length of treatment (weeks)
Overall sustained virologic response
Approximate total cost of treatment
Peginterferon and ribavirin
1-6
24-48
42%a-62%b
$36,000
Sofosbuvir and ledipasvir
1, 4
12
99%c
$94,000
Sofosbuvir and ribavirin
2
12
95%d
$86,500
Sofosbuvir and ribavirin
3
24
84%e
$173,000
Simeprevir, peginterferon, and ribavirin
1
12
80%f
$100,000
a
comparing higher-dose peginterferon plus ribavirin with standard interferon with ribavirin (P=0.02).11 comparing weight-based ribavirin with peginterferon to flat-dose ribavirin with peginterferon for treatment of genotypes 2 and 3 (P=0.252)8 c compared with adjusted historical response rate (P
