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Resistance Testing is Recommended Prior to Merck
Zepatier Treatment Only for Genotype 1a
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Jules Levin, NATAP
Yesterday the FDA approved the new Merck HCV treatment: Zepatier (elbasvir + grazoprevir)
statement in FDA Label (pdf attached): "In genotype 1a-infected subjects, the presence of one or more HCV NS5A amino acid polymorphisms at position M28, Q30, L31, or Y93 was associated with reduced efficacy of ZEPATIER for 12 weeks (Table 11, see Table 11 below), regardless of prior treatment history or cirrhosis status.” [look below to see additional details on SVR rates for patients with baseline NS5a resistance mutations.] In Table 11 below the SVR rate in patients without NS5A resistance before treatment was 98% with 12 weeks therapy, it was 100% with 16 weeks, in patients WITH NS5A resistance the SVR rate was 70% (39/56) with 12 weeks and with 16 weeks the SVR rate was 100% (6/6). This information is in the FDA Product Insert often called the label.
At the recent AASLD liver conference in Nov 2015 studies were reported showing similar results:
Ira Jacobson et al reported on SVR rates in Genotype 1a treatment-naive/prior relapsers with baseline NS5A resistance mutations: without mutations SVR rate with 12 weeks therapy was 98% and lower when mutations were found upon testing before treatment....with 16/18 weeks treatment SVR rates were 100% in GT1a patients with or without baseline NS5A resistance....
AASLD: Prevalence and Impact of Baseline NS5A Resistance-Associated Variants (RAVs) on the Efficacy of Elbasvir/Grazoprevir (EBR/GZR) Against GT1a Infection - 16 Weeks vs 12 weeks - (11/23/15)
AND here is a similar analysis by a group of international investigators of GT1a that looks at SVR rates for patients with & without resistance before treatment who are treatment-naive, prior relapsers, and prior on-treatment failures looking at SVR rates with 12 or 16/18 weeks therapy...
AASLD: The Combination of Elbasvir and Grazoprevir ± RBV Is Highly Effective for the Treatment of GT1a-Infected Patients - (11/17/15)
Resistance Testing is Recommended Prior to Treatment with Zepatier (elbasvir and grazoprevir)
This is because the results will dictate how long treatment is recommended - for 12 or 16 weeks, and if ribavirin should be added [see Table 1 below] - for the patients with NS5A resistance before treatment 16 weeks showed better SVR rates in clinical studies conducted by Merck, I will show you the differences below in SVR rates between 12 vs 16 weeks for patients with & without resistance before treatment. Taking this precaution of resistance testing so you pick the correct duration of therapy is important because this will increase SVR rates and once a patient does not achieve SVR, failure of therapy, can result in a risk for NS5A & NS3 (protease inhibitor) mutations to emerge, the emergence of the NS5A mutations can persist & may affect in a negative way future response to another NS5A inhibitor. So it is better to take the resistance test & if the patient has NS5A resistance 16 weeks therapy is better than 12.
the product label on page 1 says, recommends doing NS5A genotype resistance test before treatment with Zepatier (elbasvir and grazoprevir). You see in Table 1 below for treatment-naive & Peg/Rbv-experienced patients with baseline NS5A mutations (genotypic resistance) 16 weeks is recommended rather than the 12 weeks recommended for treatment-naive or Peg/Rbv-experienced who don’t have this resistance upon testing.
Resistance testing is available from Monogram, my understanding is insurers are covering this but Monogram offers a PAP for patients who are unable to get coverage. My understanding from personal communication is that the British Columbia Centre for Excellence in HIV/AIDS is offering resistance testing for all patients, free of charge in Canada, and outside of Canada there is a low charge much lower than it might cost elsewhere. At labs around the globe in major HCV research centers it is possible they may have the capacity to conduct resistance testing.
Monogram NS5A Resistance Test.....http://www.natap.org/2015/HCV/091115_06.htm
DOSAGE AND ADMINISTRATION
⋅ Testing prior to initiation:
⋅ Genotype 1a: Testing for the presence of virus with NS5A
resistance-associated polymorphisms is recommended. (2.1)
2.1 Testing Prior to the Initiation of Therapy
NS5A Resistance Testing in HCV Genotype 1a-Infected Patients
Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated
polymorphisms is recommended prior to initiation of treatment with ZEPATIER to determine
dosage regimen and duration [see Dosage and Administration (2.2)], Table 1. In subjects receiving
ZEPATIER for 12 weeks, sustained virologic response (SVR12) rates were lower in genotype 1a-infected
patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions
28, 30, 31, or 93 [see Microbiology (12.4)], Table 11.
Treatment Regimen and Duration of Therapy
Relapse rates are affected by baseline host and viral factors and differ between treatment regimens
and durations for certain subgroups [see Clinical Studies (14)].
Table 1 below provides the recommended ZEPATIER treatment regimen and duration based on the
patient population and genotype in HCV mono-infected and HCV/HIV-1 co-infected patients with or
without cirrhosis and with or without renal impairment including patients receiving hemodialysis.
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