As we conclude another year now past the peak of hepatitis C research, HCV Nextasked me to consider where we came from, where we are now, and where we’re headed. They wanted me to address potential new mechanisms of action for DAA therapies, shorter durations of treatment, and how to deal with the small population of treatment failures, among others. But perhaps it is best to start with the biggest and most important question: Are we done? Have we succeeded in hepatitis C?

A historical transformation of therapy in hepatitis C occurred, considering the rapid evolution of therapy from the days of PEG-interferon and ribavirin. As a reference point we should think back to the IDEAL study published in the New England Journal of Medicine in 2009 demonstrating sustained virologic response rates of 40% to 41%, with the associated toxicity well described of interferon. Now, less than 15 years later, we have multiple direct-acting, all-oral combination antiviral therapies with SVR12 rates of 95% to 100% and adverse event profiles similar to placebo. We witnessed a historic pace of development of new agents that now approach universal success. I think we all would agree these developments are remarkable and an unprecedented occurrence in medicine.

It would be hard to believe we’re not done, at least in terms of the therapies themselves. With the antivirals we have and combinations thereof, we can cure 96% to 99% of patients with HCV. We can treat patients who historically have been difficult to treat in the past — this includes end-stage renal disease, decompensated liver disease and DAA failures.

Once difficult-to-treat

We historically worried about patients who failed DAA therapy because treatment-emergent resistance gave us few retreatment options. The POLARIS-1 trial demonstrated the once difficult-to-treat DAA failure now has therapeutic options. Even patients who have previously failed two classes of antivirals (NS5A and NS3) can now achieve an SVR12 of 96%, independent of frequency or class of resistance associated substitutions.

Looking at the current mathematics of therapy, we have therapies with virologic failure rates of 2% to 4% and, now based on the POLARIS 1 trial, we can successfully retreat 96% of those DAA failures, bringing us down to about one in 1,000 patients who are left behind and will not respond to even the latest combination antiviral regimen. We have addressed every population in need of therapy and demonstrated SVR12 rates above 95% in most of these populations.

The good news is that these non-responders or recurring relapsers comprise a miniscule population. The bad news is that we don’t currently have an answer for these few patients left behind. In evaluating these few patients, I would encourage clinicians to look at these patients’ resistance profiles and closely consider all the options in our armamentarium. The likelihood of developing new salvage therapies for these patients seems remote. Development of new salvage therapies have two significant barriers: first, novel antivirals are likely to be required, and secondly, the ability to find enough patients to enroll in a clinical trial would be problematic given the very high efficacy of today’s regimens.

Duration, Mechanism of Action

What about the concept of shorter duration therapy? Despite the advances this is a topic that is still frequently discussed. As we consider the concept of shorter therapy, it is essential to remember that we currently have almost universally successful therapy with a side effect profile that is essentially similar to placebo. Shorter durations would be useful from a compliance and simplicity standpoint, however there is no enthusiasm to accept lower SVR12 rates or increased adverse event profiles to accomplish this goal.

Thinking about it practically, I would define two possible ways to shorten duration of therapy. First, would be to develop more potent antivirals that, in combination, could achieve a 95% to 100% SVR12 with 4 weeks of therapy or less. The second would be a directly-observed, single-dose parenteral therapy. Let’s consider each of these two scenarios separately.

First, a 4-week or shorter duration of therapy would require combinations of antivirals more potent than the agents of today. In C-SWIFT, we demonstrated 4 weeks of therapy produced a suboptimal SVR12 with today’s antivirals. Importantly, it taught us that a 4-week duration is plausible; however, current antivirals require a specific phenotype of patient to achieve high rates of SVR12 with a short 4-week duration. Given the biologic plausibility demonstrated by C-SWIFT one can hypothesize that it is possible to achieve high rates of SVR12 with 4-week duration therapy if we had significantly more potent antivirals.

In the second case, a single-dose parenteral therapy would be a paradigm shift for the hepatitis C field. It would involve technology that is not currently available with HCV antivirals, but has been demonstrated with HIV antivirals.

Despite the astounding success of therapies today, if we were able to achieve either of these scenarios — one, a 4-week or less treatment duration or, two, single-dose parenteral therapy — the current universally successful therapy could be displaced.

Author Info

Sean Hendrickson