Hope for HCV Patients Who Failed Therapy With Telaprevir or Boceprevir
Mark S. Sulkowski, MD - 6/28/2013
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Sky-High Expectations, Tempered by Reality
In 2011, the FDA approved the first 2 DAAs: boceprevir and telaprevir. They represented a new era of agents that directly attacked the hepatitis C virus itself, instead of working indirectly by stimulating the patient’s native antiviral immune system. With the new DAAs in combination with peginterferon/ribavirin came higher rates of SVR and the perception that hepatitis C therapy had turned a corner into a very promising future. However, not every patient benefited from that promise, and for an unfortunate group of patients who failed to achieve SVR with triple therapy, the future has been clouded with uncertainty, including questions over the clinical significance, if any, of the selection and enrichment of a population of telaprevir- and boceprevir-resistant HCV variants to protease inhibitors that they invariably developed.
A Robust Pipeline
Now, we’re beginning to recognize that these patients are not without HCV treatment options. New classes of drugs with multiple agents in development are extending and expanding the optimism first engendered by the first-generation DAAs. In clinical trials, drugs from classes as diverse as NS3/NS4A protease inhibitors, nucleos(t)ide analogues, NS5A inhibitors, and NS5B polymerase inhibitors are demonstrating greater efficacy with fewer adverse events and shorter treatment courses with and without peginterferon/ribavirin.
Initial clinical trials have reported very promising efficacy in HCV treatment-naive patients as well as those who have failed previous therapy with peginterferon/ribavirin, including “null” responders. Amidst this flood of new data, those patients who did not achieve SVR when treated with telaprevir or boceprevir finally have data that are very encouraging. At the 2013 European Association for the Study of the Liver conference, my colleagues and I presented data demonstrating that an all-oral, once-daily combination of sofosbuvir and daclatasvir, without even ribavirin, administered for 24 weeks produced 12-week SVR rates of 95% to 100% in genotype 1 HCV–infected virologic nonresponders to previous telaprevir- or boceprevir-based therapy. Indeed, the overall SVR rate was 100%. These rates remained constant even in the presence of baseline NS3 variants conferring resistance to these first-generation protease inhibitors. Although not yet presented in a scientific forum, similar treatment success was recently announced in the LONESTAR study in which triple therapy failures were treated with sofosbuvir and ledipasvir with and without ribavirin.
Reassurance for DAA “Pioneers”
Such was the excitement generated by the first DAAs that many patients and clinicians were quick to take advantage of them. Fortunately, many patients treated with telaprevir or boceprevir triple therapy achieved SVR. However, for an unfortunate minority of these DAA “pioneers,” treatment failed either due to toxicity or virologic failure. For these patients, we now have very promising data that should reassure them that they have not reached the end of their treatment options. I believe the important message here is that a cure is not only possible for patients who failed previous HCV protease inhibitors, but it may be even be “easy” in the future using combinations of oral DAAs that attack the virus at the viral polymerase (nucleos(t)ide analogues) and the NS5A glycoprotein. While we wait for the approval and greater availability of such therapies, I’ve been educating my patients about these future approaches and focusing my attention on modifiable factors to improve hepatic health, namely avoiding alcohol, achieving or maintaining a normal body mass index and, perhaps, consuming more coffee. Yes, more coffee; I’ll save further discussion of coffee and the liver for another time!
Your Thoughts?
How do you manage your DAA treatment failure patients? Are you counseling your patients to begin treatment with the new drugs as soon as they become available, or are you urging patience to wait for the optimal regimens to be identified??
Related from CCO-
HCV Approved & Phase III - Source: 2013 Annual Meeting of the European Association for the Study of the Liver*
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