By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a dual fixed-dose combination (FDC) of glecaprevir (GLE), a NS3/4A protease inhibitor, and pibrentasvir (PIB), a NS5A inhibitor, for the treatment of all major genotypes (1-6) of chronic hepatitis C infections. This FDC received a breakthrough therapy designation and a priority review. It is marketed as Mavyret. It is the third approved FDC that treats all six hepatitis C virus genotypes, after sofosbuvir/velpatasvir (Epclusa) and sofosbuvir, velpatasvir, and voxilaprevir (Vosevi).
INDICATIONS
The GLE/PIB combination is indicated for the treatment of patients with chronic hepatitis C genotypes 1, 2, 3, 4, 5, or 6 infections without cirrhosis or with compensated cirrhosis.1 It is indicated for the treatment of patients with genotype 1 infections previously treated with a NS5A inhibitor or NS3/4A protease inhibitor but not both.
DOSAGE
For treatment-naïve patients infected with genotypes 1, 2, 3, 4, 5, or 6, the recommended dose is three tablets taken once daily with food for either eight weeks (no cirrhosis) or 12 weeks (compensated cirrhosis). For patients with genotypes 1, 2, 4, 5, or 6 previously treated with interferon, ribavirin, and/or sofosbuvir but not a NS3/4A protease inhibitor or NS5A inhibitor, the dose is three tablets for eight weeks (no cirrhosis) or 12 weeks (compensated cirrhosis). For genotype 3 with the same previous treatment, the duration is 16 weeks for both cirrhotics and compensated cirrhotics. For patients with genotype 1 previously treated with an NS5A inhibitor but not a NS3/4A protease inhibitor, the duration is 16 weeks (with or without cirrhosis). For prior treatment with a NS3/4A protease inhibitor but not a NS5A inhibitor, the duration is 12 weeks (with or without cirrhosis). GLE/PIB is available as tablets each containing 100 mg of GLE and 40 mg of PIB.
POTENTIAL ADVANTAGES
GLE/PIB is approved for eight weeks of treatment duration in treatment-naïve patients with genotypes 1-6 and patients previously treated with interferon, ribavirin, and/or sofosbuvir but not a NS3/4A protease inhibitor or NS5A inhibitor with genotypes 1, 2, 4, 5, or 6 without cirrhosis. It is the first FDC approved for genotype 1 previously treated with an NS3/4A protease inhibitor. Both GLE and PIB undergo negligible renal excretion and can be used in patients with mild, moderate, or severe renal impairment, including those on dialysis.1
In vitro data indicate that PIB maintains activity against common amino acid substitutions of hepatitis C genotypes 1-6 that are known to confer resistance to currently approved NS5A inhibitors.2
POTENTIAL DISADVANTAGES
GLE/PIB is not indicated for decompensated cirrhosis and is not indicated for patients with genotype 1 who are both NS3/4A- and NS5A-experienced.1
The most frequently reported adverse events were headache, fatigue, and nausea (9-17%).1 GLE/PIB carries a higher pill burden (three tablets per day) compared to sofosbuvir/ledipasvir (Harvoni) or sofosbuvir/velpatasvir (one tablet per day).
COMMENTS
The approval of GLE/PIB was based on nine clinical trials that studied more than 2,300 subjects across all major genotypes 1-6, who were with or without cirrhosis, who were treatment-naïve and selected treatment-experienced, and who presented with stage 4 or 5 chronic kidney disease.1
For treatment-naïve subjects or those previously treated with interferon, ribavirin and/or sofosbuvir but not a NS3/4A protease inhibitor or NS5A inhibitor without cirrhosis, sustained viral response at 12 weeks after completion of treatment (SVR12) was 99% for genotype 1 after eight weeks of treatment. For subjects with genotypes 2, 4, 5, or 6 without cirrhosis, SVR12 ranged from 93-100% for eight weeks of treatment. For treatment-naïve subjects or those previously treated with interferon, ribavirin, and/or sofosbuvir but not a NS3/4A protease inhibitor or NS5A inhibitor with genotypes 1, 2, 4, 5, or 6 and compensated cirrhosis, SVR12 ranged from 99-100% for 12 weeks of treatment. For genotype 3 treatment-naïve subjects without cirrhosis, SVR12 was 94.9% (eight weeks), 95.3% (12 weeks), and comparable to sofosbuvir/daclatasvir for 12 weeks (96.5%).
In subjects with genotype 3 who were treatment-naïve with cirrhosis, SVR12 was 98% with 12 weeks of treatment and 96% for subjects previously treated with interferon, ribavirin, and/or sofosbuvir but not a NS3/4A protease inhibitor or NS5A inhibitor with or without cirrhosis (16 weeks of treatment). For subjects with genotype 1 who were either NS3/4A protease inhibitor- or NS5A inhibitor-experienced (not both), SVR12 was 92% and 94%, respectively.
In the study of subjects with chronic kidney disease, those who were treatment-naïve or previously treated with interferon, ribavirin, and/or sofosbuvir but not a NS3/4A protease inhibitor or NS5A inhibitor with or without cirrhosis, overall SVR12 was 98%.
CLINICAL IMPLICATIONS
GLE/PIB is currently the only FDA-approved eight-week regimen for patients without cirrhosis infected with genotypes 1-6 who are treatment-naïve and those with genotypes 1, 2, 4, 5, or 6 previously treated with inferferon, ribavirin, and/or sofosbuvir but not a NS3/4A protease inhibitor or NS5A inhibitor. Currently, American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) guidelines recommend FDC of sofosbuvir/velpatasvir for 12 weeks across genotypes 1-6 for initial treatment.3
For those with compensated cirrhosis, both FDCs are recommended for 12 weeks. GLE/PIB may be preferable for chronic kidney disease patients. It is the second FDC approved for genotype 1 previously treated with a NS5A, after Vosevi. However, the latter is approved for a shorter treatment duration (12 weeks vs. 16 weeks) and for all major genotypes.4 GLE/PIB is the first for prior treatment with a NS3/4A protease inhibitor.
The hepatitis C guidance of the AASLD/IDSA recommends Harvoni or Epclusa for NS3/4A protease inhibitor-experienced patients, but indicated that there are very limited options for patients who have failed on NS5A inhibitors.3 The role of GLE/PIB has not been updated by AASLD/IDSA at the time of this review. The price is $13,200 per month or $26,400 per eight-week treatment course, which is generally less than other drugs in this class.
REFERENCES
- Mavyret Prescribing Information. AbbVie Inc. August 2017.
- Ng TI, Krishnan P, Pilot-Matias T, et al. In vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS5A inhibitor pibrentasvir. Antimicrob Agents Chemother 2017;61(5). pii: e02558-16. doi: 10.1128/AAC.02558-16.
- American Association for the Study of Liver Diseases. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: http://bit.ly/1kx8zy3. Accessed Sept. 6, 2017.
- Vosevi Prescribing Information. Gilead Sciences Inc. July 2017.
The FDA has approved a dual fixed-dose combination of glecaprevir, a NS3/4A protease inhibitor, and pibrentasvir, a NS5A inhibitor, for the treatment of all major genotypes (1-6) of chronic hepatitis C infections.
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