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Study sheds light on RAVs in treatment-naive, experienced patients

BARCELONA — Treatment-naive patients with resistance-associated variants may be treated with a number of novel direct-acting antiviral therapies, regardless of genotype and the nature of their RAVs. For treatment-experienced patients, however, certain factors need to be considered before initiating retreatment.

Julia Dietz, MD, of Goethe University Hospital in Frankfurt, Germany, presented findings culled from the European RAV database. The overall cohort included 3,459 patients, with 2,846 patients in the genotype 1 group, 99 for genotype 2, 456 for genotype 3, 139 for genotype 4, seven for genotype 5 and one patient with genotype 6 HCV.

The researchers noted that RAVs vary by genotypes, but that pre-existing RAVs often yield virologic failure after therapy. They investigated the frequency of NS3, NS5A and NS5B RAVs among treatment-naive and treatment-experienced patients. There were 1,950 naive patients included in the study. Among the experienced patients, 311 failed Victrelis (boceprevir, Merck)/Incivek (telaprevir, Vertex) plus pegylated interferon-ribavirin, 62 failed Sovaldi (sofosbuvir, Gilead) plus PEG-ribavirin, 100 failed sofosbuvir plus ribavirin, 55 failed on Olysio (simeprevir, Janssen) plus sofosbuvir with or without ribavirin, 51 failed Daklinza (daclatasvir, Bristol Myers Squibb) with or without ribavirin, 114 failed Harvoni (ledipasvir/sofosbuvir, Gilead) with or without ribavirin and 30 failed Viekira Pak (paritaprevir/ombitasvir/dasabuvir, Abbvie, also known as the 3-D regimen in this study) with or without ribavirin.  

Among naive patients, for genotype 1, the range of RAVs was as low as 3% (NS3 RAVs in genotype 1b patients) and as high as 53% (NS5B RAVs in genotype 1B patients). The rate was 84% for genotype 2, 9% for genotype 3 and 66% for genotype 4. The overall rate of pre-existing RAVs in the naive group was 38%. 

RAVs were found in 27% to 42% of genotype 1a patients treated with boceprevir and telaprevir at a median sampling time of 12 months after treatment.

For patients who failed sofosbuvir-based regiments, no RAVs were detected in GT 1a patients. Sixty-one percent of patients with genotype 1b HCV had NS5B RAVs, while 11% of those with genotype 3 HCV had those RAVs after treatment with sofosbuvir. These evaluations took place 6 months after treatment.

In patients treated with simeprevir and sofosbuvir, 82% of patients with genotype 1a and 44% of genotype 1b patients had NS3 RAVs.

The researchers also compared RAVs in patients treated with daclatasvir/sofosbuvir with those treated with ledipasvir/sofosbuvir. The rates of RAVs were above 80% for patients with genotype 1 disease in both groups. Also notably, among patients with genotype 3 HCV, NS5A RAVs occurred in 95% who failed daclatasvir/sofosbuvir, compared with just 7% of those who failed ledipasvir/sofosbuvir.

“In ledipasvir/sofosbuvir-treated patients, resistance is lacking,” Dietz said. “This is probably due to the not strong antiviral activity of ledipasvir in genotype 3.”

For the 3-D regimen, samples were taken 3 months after treatment. In genotype 1a patients, resistance rates ranged from 38% (NS5B variants) to 100% (NS5A variants). The range was from 56% (NS3) to 89% (NS5A) for genotype 1b patients previously treated with the 3D regimen.

Dietz also reported on retreatment options according to the presence of RAVs.

“All DAA-naive patients, as well as those treated with boceprevir, telaprevir, sofosbuvir and ribavirin with peginterferon could be re-treated under the consideration of RAVs,” Dietz said. She noted that more challenges exist for individuals who previously received simeprevir, daclatasivr and ledipasvir in combination with sofosbuvir. Clinicians should consider the patient’s genotype when administering therapy to a patient who failed therapy with the 3-D regimen.

“To conclude, the frequency of RAVs in DAA-naive patients ranged between 1% and 80% according to HCV genotype,” Dietz said. “We mainly observed low- to medium-level resistance variants. RAV-free treatment options are available for almost all of these patients.”

The frequency of RAVs in experienced patients is high, according to Dietz. “There was a persistence of protease inhibitor RAVs in HCV genotype 1 patients for several months,” she said. “There are typical patterns of NS5A RAVs according to HCV genotype and subtype with long persistence. No NS5A RAVs were reported in after ledipasvir treatment in patients with genotype 3.”

Dietz added that depending on the initial DAA regimen, RAV-free retreatment options may be restricted for experienced patients.

Reference:

Susser S, et al. Abstract PS007. Presented at: International Liver Congress; April 13-17, 2016; Barcelona.

Disclosures: Dietz reports no relevant financial disclosures.