1. Patients with hepatitis C genotype 1 treated with a combination of faldaprevir, deleobuvir and ribavirin achieved sustained virologic response rates up to 69%.
2. Patients with viral subtype 1b had higher response rates than patients with 1a. Patients who possessed the IL28B genotype CC responded better than those with non CC genotypes.
3. 94% of patients who underwent treatment with faldaprevir and delbuvir experienced adverse events.
Evidence Rating Level: 2 (Good)
Hepatitis C has become a treatable disease. The now conventional therapy consists of ribavirin, a guanosine analogue that inhibits viral replication, combined with pegylated interferon administered over several months. The goal of such therapy is to achieve a sustained virologic response (SVR) defined as undetectable levels of viral RNA in the patients’ blood after cessation of therapy. However, patients fail therapy or experience relapses due to variables that include the inability to tolerate therapy, the viral subtype, and the patient’s own genotype of the innate immune cytokine interleukin 28B (IL28B). Hepatitis C subtypes 2, 3, and 4 generally respond to conventional therapy, while subtype 1 requires the addition of a viral protease inhibitor.
Study Rundown: This study examined the efficacy and safety of an interferon-free regimen for hepatitis C genotype 1 that consisted of faldaprevir (a protease inhibitor), deleobuvir (an RNA polymerase inhibitor) and ribavirin. This was a phase 2 trial that was not blinded and included no standard therapy comparison arm, but showed promising results. The rates of SVR achieved with this novel regimen (52-65%) appear comparable to those achieved with interferon-containing regimens (68-75%). The results suggest the new regimen might be a viable alternate therapeutic option for genotype 1 patients who have contraindications or intolerances to interferon. However, given the high rate of adverse events in this study, it remains to be seen if it can effectively replace standard therapy. The results also reinforce what prior studies have shown that viral subtype 1b is more responsive to therapy than 1a. Interestingly, this study showed that the IL28B polymorphism affects the rate of SVR, suggesting that innate immunity is likely an important factor even in interferon-free regimens, though further study will need to clarify how.
Background Reading: Antiviral effect, safety and pharmacokinetics of 5 days oral administration of deleobuvir (BI 207127), an investigational HCV RNA polymerase inhibitor, in patients with chronic hepatitis C
In-Depth [phase 2 randomized open-label trial]: This study enrolled 362 patients infected with HCV genotype 1 from 48 sites across multiple countries. Patients were stratified by viral subtype (1a or 1b) and by their IL28B genotypes (CC or non CC) and assigned to receive one of 5 therapies: 1) faldaprevir + deleobuvir dosed 3 times daily + ribavirin for 16 weeks (TID16W), 2) 28 weeks (TID28W), or 3) 40 weeks (TID40W), 4) faldaprevir + deleobuvir dosed twice daily + ribavirin (BID28W), or 5) faldaprevir + deleobuvir three times daily without ribavirin (TID28W-NR). The primary efficacy outcome was SVR at 12 weeks after therapy completion. Additionally, researchers monitored for adverse events, and also for resistance via sequencing. They found there was no significant difference in the proportion of patients who attained SVR at 12 weeks between the treatment groups that included ribavirin (range 52%-69%). The patients receiving the regimen without ribavirin experienced a lower rate of SVR (59% in TID28W vs 39% in TID28W-NR p=0.03). Additionally, patients with viral subtype 1a had lower rates of SVR than those with 1b, except in the TID40W group. SVR rates were also higher in patients with the IL28B genotype CC than patients with the non CC genotype. 94% of patients experienced adverse events, the most common of which were gastrointestinal and dermatologic reactions. While less common, hematologic cell count reductions were the most prohibitive adverse effect.
By Akira Shishido, MD and Mitalee Patil
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