EASL 2014 - CARE Liver Disease Faculty. Abstract O55

EASL 2014: Abstract O55. Successful retreatment with sofosbuvir of HCV Genotype-1 Infected patients who failed prior therapy with peginterferon+ribavirin plus 1 or 2 additional direct-acting antiviral agents.

S. Pol1, M. Sulkowski2, T. Hassanein3, E. Gane4, N. Liyun5, H. Ho5, B. Kanwar5, D. Brainard5, M. Subramanian5, W.T. Symonds5, J.G. McHutchison5, M. Bennett6, I.M. Jacobson7

1University of Paris, Paris, France, 2Johns Hopkins University School of Medicine, Baltimore, MD, 3Southern California Liver Centers, Coronado, CA, United States, 4Auckland City Hospital, Aukland, New Zealand,5Gilead Sciences, Foster City, 6Medical Associates Research Group, San Diego, CA, 7Weill Cornell Medical College, New York, NY, United States

Background and Aims: GT1 patients who failed prior treatment with peginterferon (PEG-IFN) + ribavirin (RBV) + a protease inhibitor (PI) have no available treatment options. The aim of this study was to evaluate the efficacy of the 12-week sofosbuvir (SOF) + PEG/RBV regimen in patients who had failed prior 3- and 4-drug regimens.

Results: A total of 57 GT1 prior treatment failure patients entered the study. All patients failed prior therapy with PEG/RBV in combination with a PI with or without an NS5a polymerase inhibitor (ledipasvir) or a non-nucleoside NS5b polymerase inhibitor (tegobuvir). The average duration of prior therapy was 202 days (SD +/- 144 days). Sixteen patients (30%) received more than 1-course of prior therapy. The majority were male (72%), genotype 1a (93%) and IL28B non-CC (95%). To date, SVR4 rates are 96% (22/23) for the patients who have reached the 4-week post treatment visit (see table).

Conclusions: The 12-week regimen of SOF+PEG+RBV results in high SVR4 rates in previously treated HCV GT1- infected patients despite single or multiple baseline resistant mutations and other unfavorable baseline characteristics.

Although this study is small and applies to a variety of patient-types, there are a few important take-home points. The first point is that sofosbuvir (SOF) failure does not mean that SOF cannot be used again. The fact that all 19 genotype 1 SOF-experienced patients were cured with the combination of sofosbuvir/ledipasivir (SOF/LDV) FDC is very reassuring. This supports the concept that the barrier to resistance with SOF is so high that resistance will not be a problem with this drug and will allow patients to be retreated with sofosbuvir-containing regimens. Ribavirin was added with retreatment, which certainly makes some sense but future studies will clarify whether it is actually necessary.

Unfortunately the results were not quite as good as in the other 2 arms. We all have many patients with early hepatic decompensation and this study shows that we can treat and cure at least a proportion with SOF/LDV for 12 weeks. The most reassuring thing was the safety profile in these sick patients.

What remains to be seen is whether SVR at this late stage reverses the course of disease. The data are definitely promising but if these patients end up needing transplants anyway, treatment post-transplant may be a simpler strategy. For the genotype 3 patients, the results were a bit surprising. As we know, the relapse rate is high with SOF and ribavirin alone. Ledipasivir is not very active against genotype 3. The SVR rate with the FDC alone was 64% but jumped to 100% with the addition of ribavirin.

Although this is certainly a great result, one wonders whether this will hold up in larger trials. In the original ELECTRON trial, the SVR rate was 100% with SOF/RBV alone in genotype 3 patients and this did not pan out in larger studies. One has to wonder if the genotype 3 patients from New Zealand may have a different virus than the genotype 3 we see elsewhere and if so, it may is hard to know how to interpret these results. My take would be that although SOF/LDV may add something to SOF/RBV for genotype 3, it is likely not the final answer.
— CARE Liver Disease Faculty Commentary