Pharmacology Consult

New directions in hepatitis C treatment

Hepatitis C virus is an important cause of hepatic fibrosis, cirrhosis and end-stage liver disease.

Approximately 175 million patients worldwide are infected with HCV. Different genotypes exist that vary in difficulty of treatment. Genotype 1 is the most common in the United States, found in approximately 75% of patients.

Leah Molloy

Leah Molloy

Compared with genotypes 2 and 3, in which approximately 80% of patients achieve sustained virologic response (SVR), fewer than half of patients infected with HCV genotype 1 typically achieve SVR using traditional therapy.

Existing treatment options

Historically, a combination of peginterferon-alpha (peg-INF) and ribavirin has been the mainstay of HCV therapy. Interferon-alpha is an immunomodulator that may be conjugated with polyethylene glycol to form peg-INF to prolong its half-life and allow weekly injections. Although the mechanism of ribavirin in the management of HCV infection is incompletely understood, the addition of this agent optimizes the effects of peg-INF and limits relapse of infection. These traditional treatment modalities remain vital components of successful antiviral therapy, but do not come without important adverse effects involving neuropsychiatric disorders, autoimmune disease, infections, teratogenicity and the inconvenience of long-term parenteral therapy.

In 2011, the first direct-acting antiviral agents for the treatment of chronic hepatitis C caused by HCV genotype 1 were approved. Telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir (Victrelis, Merck) are protease inhibitors (PIs) targeted against the HCV NS3/4A protease enzyme. When evaluated in separate studies, the addition of each of these PIs to the treatment backbone of ribavirin plus peg-INF yielded significantly greater SVR than a regimen of ribavirin plus peg-INF alone.

Although the development of these agents represents an important breakthrough in the management of HCV infection, they have limitations. Both PIs present a significant pill burden, up to 12 capsules daily depending on regimen, and require multiple doses per day. As is typical of PIs, drug-drug interactions must be carefully managed because telaprevir and boceprevir are both potent CYP3A inhibitors and also are partially metabolized by CYP3A. In terms of tolerability, anemias have been described with both PIs, and telaprevir carries a black box warning for severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Simeprevir

Similar to telaprevir and boceprevir, simeprevir (Olysio, Janssen) is an HCV NS3/4A PI. Simeprevir was approved by the FDA in November for the treatment of chronic infection with HCV genotype 1, combined with peg-INF and ribavirin.

Simeprevir is a CYP3A substrate and inhibitor; however, it inhibits intestinal CYP3A only with no effect on hepatic CYP3A enzymes, which offers easier management of drug-drug interactions. For example, close monitoring and use of lowest effective doses is recommended when HMG-CoA reductase inhibitors are co-administered with simeprevir while co-administration of these agents combined with telaprevir is simply contraindicated. However, simeprevir has more clinically significant interactions with the P-glycoprotein (P-gp) transport system than the other PIs, warranting closer monitoring of patients concomitantly receiving P-gp substrates. Simeprevir offers an easy administration regimen of one 150-mg capsule to be given once daily with food. Besides a simpler regimen and fewer drug-drug interactions, simeprevir may be more tolerable in terms of adverse effects, the most common of which were photosensitivity, rash and nausea. Although insufficient data exist to offer recommendations for sulfa-allergic patients, it should be noted that simeprevir contains a sulfonamide moiety.

The approval was based on a series of placebo-controlled studies wherein significantly more patients who received simeprevir combined with peg-INF and ribavirin achieved SVR at 12 weeks after the end of treatment (SVR12) compared with those who received INF and ribavirin alone. This higher SVR12 attainment with the addition of simeprevir was observed among both treatment-naive patients (80% vs. 50%) and patients with history of relapse (79% vs. 37%). Patients received simeprevir combined with peg-INF and ribavirin for 12 weeks, followed by an additional 12 to 36 weeks of peg-INF and ribavirin. Most patients were eligible for the shorter 24-week total duration of therapy, and their SVR attainment was more than 80% in all studies.

Also of note, dosage recommendations have not been made for patients with moderate-to-severe liver disease nor those of East Asian descent, as these populations tend to have greater systemic drug exposure. Patients with HCV genotype 1a should be screened to identify those infected with virus harboring the NS3 Q80K polymorphism. Alternative therapy is recommended in these cases because the addition of simeprevir to peg-INF and ribavirin did not offer any benefit in the presence of this polymorphism.

Sofosbuvir

Sofosbuvir (Sovaldi, Gilead Sciences) is the first nucleotide analogue HCV NS5B polymerase inhibitor and the only direct-acting antiviral agent approved for treatment of HCV genotypes other than genotype 1. It was approved in December for the treatment of chronic hepatitis C infection combined with peg-INF and/or ribavirin, depending on HCV genotype. Sofosbuvir is administered as one 400-mg tablet once daily that can be given without regard to food. Sofosbuvir metabolism does not involve the CYP450 enzyme system, and sofosbuvir is a P-gp substrate, but its active metabolite is not.

Patients infected with HCV genotypes 1 or 4 should receive sofosbuvir combined with both peg-INF and ribavirin for 12 weeks, whereas genotypes 2 and 3 may be managed with sofosbuvir combined with ribavirin only, per the results of two phase 3 studies. In the first, a single-group open-label study of 327 patients, 98% of whom were infected with HCV genotype 1 or 4, all patients received a 12-week treatment course of sofosbuvir combined with ribavirin and peg-INF with 90% attainment of SVR12.

The second study compared a 12-week course of sofosbuvir plus ribavirin to a 24-week course of ribavirin plus peg-INF among 499 patients infected with HCV genotypes 2 or 3 and found identical success rates of 67% attainment of SVR12. Because of the substantial difference in SVR12 attainment between the two genotypes (97% for genotype 2, 56% for genotype 3), a 12-week course of sofosbuvir with ribavirin is recommended only for genotype 2, whereas a 24-week course is recommended for genotype 3.

The addition of sofosbuvir to the growing armamentarium of anti-HCV agents presents the first all-oral, INF-free treatment option for HCV infection with a notably shorter duration of therapy than previously available regimens.

Treatment guidelines

To keep pace with new drug development, the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases have committed to provide online, up-to-date recommendations as exciting progress continues in this new era of HCV treatment.

References:

Bacon BR. N Engl J Med. 2011;364:1207-1217.
FDA. Antiviral Drugs Advisory Committee Meeting Briefing Document. Simeprevir (TMC435): Treatment of Patients with Chronic Hepatitis C. Oct. 24, 2013. Available at:www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Antiviral
DrugsAdvisoryCommittee/UCM371624.pdf.
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2013.
Jacobson IM. N Eng J Med. 2011;364:2405-2416.
Munir S. Virol J. 2010;7:296.
Olysio [package insert]. Titusville, NJ: Janssen Products; 2013.
Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
Sovaldi [package insert]. Foster City, CA: Gilead Sciences Inc.; 2013

For more information:

Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit.

Disclosure: Molloy reports no relevant financial disclosures.

Hepatitis C virus is an important cause of hepatic fibrosis, cirrhosis and end-stage liver disease.

Approximately 175 million patients worldwide are infected with HCV. Different genotypes exist that vary in difficulty of treatment. Genotype 1 is the most common in the United States, found in approximately 75% of patients.

Leah Molloy

Leah Molloy

Compared with genotypes 2 and 3, in which approximately 80% of patients achieve sustained virologic response (SVR), fewer than half of patients infected with HCV genotype 1 typically achieve SVR using traditional therapy.

Existing treatment options

Historically, a combination of peginterferon-alpha (peg-INF) and ribavirin has been the mainstay of HCV therapy. Interferon-alpha is an immunomodulator that may be conjugated with polyethylene glycol to form peg-INF to prolong its half-life and allow weekly injections. Although the mechanism of ribavirin in the management of HCV infection is incompletely understood, the addition of this agent optimizes the effects of peg-INF and limits relapse of infection. These traditional treatment modalities remain vital components of successful antiviral therapy, but do not come without important adverse effects involving neuropsychiatric disorders, autoimmune disease, infections, teratogenicity and the inconvenience of long-term parenteral therapy.

In 2011, the first direct-acting antiviral agents for the treatment of chronic hepatitis C caused by HCV genotype 1 were approved. Telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir (Victrelis, Merck) are protease inhibitors (PIs) targeted against the HCV NS3/4A protease enzyme. When evaluated in separate studies, the addition of each of these PIs to the treatment backbone of ribavirin plus peg-INF yielded significantly greater SVR than a regimen of ribavirin plus peg-INF alone.

Although the development of these agents represents an important breakthrough in the management of HCV infection, they have limitations. Both PIs present a significant pill burden, up to 12 capsules daily depending on regimen, and require multiple doses per day. As is typical of PIs, drug-drug interactions must be carefully managed because telaprevir and boceprevir are both potent CYP3A inhibitors and also are partially metabolized by CYP3A. In terms of tolerability, anemias have been described with both PIs, and telaprevir carries a black box warning for severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Simeprevir

Similar to telaprevir and boceprevir, simeprevir (Olysio, Janssen) is an HCV NS3/4A PI. Simeprevir was approved by the FDA in November for the treatment of chronic infection with HCV genotype 1, combined with peg-INF and ribavirin.

Simeprevir is a CYP3A substrate and inhibitor; however, it inhibits intestinal CYP3A only with no effect on hepatic CYP3A enzymes, which offers easier management of drug-drug interactions. For example, close monitoring and use of lowest effective doses is recommended when HMG-CoA reductase inhibitors are co-administered with simeprevir while co-administration of these agents combined with telaprevir is simply contraindicated. However, simeprevir has more clinically significant interactions with the P-glycoprotein (P-gp) transport system than the other PIs, warranting closer monitoring of patients concomitantly receiving P-gp substrates. Simeprevir offers an easy administration regimen of one 150-mg capsule to be given once daily with food. Besides a simpler regimen and fewer drug-drug interactions, simeprevir may be more tolerable in terms of adverse effects, the most common of which were photosensitivity, rash and nausea. Although insufficient data exist to offer recommendations for sulfa-allergic patients, it should be noted that simeprevir contains a sulfonamide moiety.

The approval was based on a series of placebo-controlled studies wherein significantly more patients who received simeprevir combined with peg-INF and ribavirin achieved SVR at 12 weeks after the end of treatment (SVR12) compared with those who received INF and ribavirin alone. This higher SVR12 attainment with the addition of simeprevir was observed among both treatment-naive patients (80% vs. 50%) and patients with history of relapse (79% vs. 37%). Patients received simeprevir combined with peg-INF and ribavirin for 12 weeks, followed by an additional 12 to 36 weeks of peg-INF and ribavirin. Most patients were eligible for the shorter 24-week total duration of therapy, and their SVR attainment was more than 80% in all studies.

Also of note, dosage recommendations have not been made for patients with moderate-to-severe liver disease nor those of East Asian descent, as these populations tend to have greater systemic drug exposure. Patients with HCV genotype 1a should be screened to identify those infected with virus harboring the NS3 Q80K polymorphism. Alternative therapy is recommended in these cases because the addition of simeprevir to peg-INF and ribavirin did not offer any benefit in the presence of this polymorphism.

Sofosbuvir

Sofosbuvir (Sovaldi, Gilead Sciences) is the first nucleotide analogue HCV NS5B polymerase inhibitor and the only direct-acting antiviral agent approved for treatment of HCV genotypes other than genotype 1. It was approved in December for the treatment of chronic hepatitis C infection combined with peg-INF and/or ribavirin, depending on HCV genotype. Sofosbuvir is administered as one 400-mg tablet once daily that can be given without regard to food. Sofosbuvir metabolism does not involve the CYP450 enzyme system, and sofosbuvir is a P-gp substrate, but its active metabolite is not.

Patients infected with HCV genotypes 1 or 4 should receive sofosbuvir combined with both peg-INF and ribavirin for 12 weeks, whereas genotypes 2 and 3 may be managed with sofosbuvir combined with ribavirin only, per the results of two phase 3 studies. In the first, a single-group open-label study of 327 patients, 98% of whom were infected with HCV genotype 1 or 4, all patients received a 12-week treatment course of sofosbuvir combined with ribavirin and peg-INF with 90% attainment of SVR12.

The second study compared a 12-week course of sofosbuvir plus ribavirin to a 24-week course of ribavirin plus peg-INF among 499 patients infected with HCV genotypes 2 or 3 and found identical success rates of 67% attainment of SVR12. Because of the substantial difference in SVR12 attainment between the two genotypes (97% for genotype 2, 56% for genotype 3), a 12-week course of sofosbuvir with ribavirin is recommended only for genotype 2, whereas a 24-week course is recommended for genotype 3.

The addition of sofosbuvir to the growing armamentarium of anti-HCV agents presents the first all-oral, INF-free treatment option for HCV infection with a notably shorter duration of therapy than previously available regimens.

Treatment guidelines

To keep pace with new drug development, the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases have committed to provide online, up-to-date recommendations as exciting progress continues in this new era of HCV treatment.

References:

Bacon BR. N Engl J Med. 2011;364:1207-1217.
FDA. Antiviral Drugs Advisory Committee Meeting Briefing Document. Simeprevir (TMC435): Treatment of Patients with Chronic Hepatitis C. Oct. 24, 2013. Available at:www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Antiviral
DrugsAdvisoryCommittee/UCM371624.pdf.
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2013.
Jacobson IM. N Eng J Med. 2011;364:2405-2416.
Munir S. Virol J. 2010;7:296.
Olysio [package insert]. Titusville, NJ: Janssen Products; 2013.
Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
Sovaldi [package insert]. Foster City, CA: Gilead Sciences Inc.; 2013

For more information:

Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit.

Disclosure: Molloy reports no relevant financial disclosures.