Largest DAA study to date in HCV genotype 4

Posted on May 17, 2015

Largest study to date shows that the two direct-acting antiviral drug-only regimen (ombitasvir plus paritaprevir) is effective and well tolerated in both treatment-naive and treatment-experienced patients with HCV genotype 4 infection without cirrhosis. Note that patients also received low-dose ritonavir to increase paritaprevir peak and trough concentrations and overall drug exposure. HCV genotype 4 is a heterogeneous genotype with multiple subtypes, and this study included a range of genotype 4 subtypes based on phylogenetic analysis.

Globally, HCV genotype 4 accounts for roughly 13% of all HCV infections; a large proportion of the worldwide HCV epidemic.

  • HCV genotype 4 is common in the Middle East, North Africa, and sub-Saharan Africa
    • Responsible for more than 90% of HCV infections in Egypt
    • Accounts for 14–20% of HCV infections in some European countries.

While guidelines recommend the use of new DAA therapies in combination with pegylated interferon, ribavirin, or both, these regimens may be poorly tolerated because of symptoms associated with pegylated interferon (flu-like symptoms, psychiatric symptoms, and fatigue) and ribavirin (hematological side-effects, such as anemia).

Results of a multicenter, ongoing phase 2b, randomized, open-label study (PEARL-I) of an all-oral, interferon-free regimen (ombitasvir plus paritaprevir) in genotype 4-infected treatment-naive and pegylated interferon plus ribavirin “treatment-experienced” null responders, partial responders, or relapsers without cirrhosis, were recently published in the journal Lancet (Hézode C et al. Lancet. 2015 Mar 30. pii: S0140-6736(15)60159-3. [Epub ahead of print]).

  • Patients (18-70 years) were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. The first participant was screened in August, 2012, and the last participant completed treatment in March, 2014.
  • Treatment-naïve patients received a 12-week regimen of once-daily ombitasvir (25 mg), plus paritaprevir (150 mg), plus ritonavir (100 mg) with and without twice-daily, weight-based ribavirin.
  • All treatment-experienced patients received a 12-week regimen of once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with twice-daily weight-based ribavirin.
  • The primary protocol-specified efficacy endpoint was SVR12.

Of 135 patients with HCV genotype 4 who were enrolled and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment experienced patients (23 null responders) received the ribavirin-containing regimen. 68 (50%) of 135 patients were infected with viral subtype 4d and 50 (37%) with subtype 4a based on phylogenetic analysis. Demographic characteristics were similar across treatment groups.

  • In treatment-naive patients, SVR12 rates were 100% (42/42 [95% CI 91·6–100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3–97·5]) in the ribavirin-free regimen; there was no statistical difference in SVR12 rates between these two treatment groups after adjusting for interleukin 28B genotype (mean difference −9·16% [95% CI −19·61 to 1·29]; P = 0·086)
    • Three treatment-naive patients who received ombitasvir plus paritaprevir plus ritonavir without ribavirin had virological failure
  • All treatment-experienced patients (49/49; 100% [95% CI 92·7–100]) in the ribavirin-containing group achieved SVR12
  • No relapses between post treatment week 12 and post treatment week 24 occurred in treatment-naive patients in either treatment group; the treatment-experienced patients had not yet reached post treatment week 24, but no relapses had been observed after post treatment week 12 in this group of patients
  • Most common treatment-emergent adverse events were headache (14 [29%] of 49 treatment-experienced patients vs 14 [33%] of 42 treatment-naive patients given combination plus ritonavir), asthenia (10 [24%] vs 16 [33%]), fatigue (3 [7%] vs 9 [18%]), insomnia (2 [5%] vs 8 [16%]), and nausea (4 [9%] vs 7 [17%])
  • Treatment-emergent adverse events were mostly mild in severity and none led to trial discontinuation or dose interruption
  • No laboratory abnormalities above grade 3 were reported

The results of this study indicate that HCV genotype 4-infected treatment-naive and treatment-experienced patients without cirrhosis can achieve high SVR12 rates following treatment with an all-oral, interferon-free, 12-week regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin. Study authors note that the 100% (42/42) SVR12 rate observed with the ribavirin-containing regimen in treatment-naive and treatment-experienced patients suggests that this regimen provides the highest certainty of achieving sustained virological response in patients infected with diverse HCV genotype 4 subtypes. Only four patients required ribavirin dose modification for anemia or a hemoglobin decrease. Study authors also noted that future trials of this two-direct-acting antiviral drug regimen should be undertaken to assess its efficacy and safety in genotype 4-infected patients with cirrhosis.

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