The 2013 International Liver Congress (ILC2013) has come to a close, and the conference has made one thing quite clear – if you care about hepatitis C (HCV) treatment, you should be paying close attention to the news about the second generation of direct acting antivirals (DAA). Although the approval of the first generation DAAs two years ago revolutionized HCV care, boceprevir and telaprevir did not provide an instantaneous solution to all HCV treatment problems.
In fact, real-world studies presented at ILC2013 suggest that triple therapies using those DAAs, in combination with peg-interferon and ribavirin (PR), are far less promising than scientists expected from the clinical trial results. To quote Dr. Laurent Castera, a member of the EASL scientific committee, “There’s been a lot of hope regarding triple therapy… but the paradox is that [for] the patients who most needed treatment, patients with cirrhosis and treatment experienced patients, the results have been pretty disappointing.” Furthermore, triple therapies are turning out to be very difficult to manage in clinical practice.
Studies presented at ILC2013 suggest that the problems with real-world use of current triple therapies are threefold. The first concern is that sustained viral response (SVR) rates are much lower in the neediest patients, those with compensated cirrhosis and liver fibrosis, than they were in the original trials. Although triple therapies were more successful than the standard of care, the SVR rates in presented studies were still often well below 50 percent. One large French trial found that only around 40 percent of patients with compensated cirrhosis achieved SVR, and another study found success in less than a quarter of patients with severe fibrosis. Importantly, the degree of treatment success varied with the type of failure patients had previously experienced on PR therapy. Individuals who had relapsed after treatment were much more likely to respond to triple therapy with either telaprevir or boceprevir than those who had either never responded only had a partial response. Additionally both drugs were more likely to induce a positive response in genotype1b patients than in patients with genotype 1a.
The second problem associated with triple therapy is the extraordinarily high rate of adverse events. One large American study found that almost 80 percent of treated patients experienced noticeable side effects, and that severe side effects were more common in patients with cirrhosis. In particular, both that study and another European study found that there was a high rate of sepsis associated with the use of triple therapy in cirrhotic patients.
The third problem found with real-world triple therapy follows naturally from the first two. A large number of patients on these regimens discontinue use of the drugs, either because of lack of efficacy or adverse events. The intense monitoring required to prevent serious side effects, such as anemia and sepsis, can also be off-putting to both doctors and patients, particularly in cases where there is only a low expectation that SVR will be achieved.
Although these results are discouraging, they could not distract from the environment of hope and excitement that permeated the discussions of HCV treatment at ILC2013. To quote Dr. Castera, “The good news is that in patients who fail triple therapy we have rescue treatments.” Such treatments are still investigational, but they take advantage of the next generation of DAAs – some of which are already proving highly effective in patients who have had little to no success on existing regimens.
It’s truly a thrilling time to be involved in HCV treatment research. Not only are a number of new DAAs are coming down the pipeline, but researchers are also changing the way that these drugs can be used. Between the development of interferon-free regimens and the flexibility allowed by response guided therapy (RGT), it seems clear that within the next few years, treatment will be easier for doctors and patients alike.