Hepatitis C Treatment: Hope on the Horizon

Digestive Disease Week (DDW) 2014

Donald M. Jensen, MD; Lauri R. Graham

Disclosures

June 16, 2014

In This Article

Editor's Note: The treatment for hepatitis C is evolving rapidly, and interferon-free options are now finally possible, with impressive sustained viral response (SVR) rates. Medscape spoke with Donald M. Jensen, MD, Professor of Medicine and Director of the Department of Hepatology at the University of Chicago, about the new and forthcoming treatment options for hepatitis C, some of which were presented at the recent Digestive Disease Week (DDW) meeting; the collaboration of care among providers in the treatment of patients; and an assessment of the cost now versus the prior standard of care.

Interferon-Free Options At Last

Medscape: The ION, SAPPHIRE, TURQUOISE, and PEARL studies were for hepatitis C genotype 1 and tested interferon-free regimens in specific patient populations (such as treatment-naive, treatment-experienced, and cirrhotic patients). The results of these studies have now been shared, some of which were presented at DDW. Could you briefly describe the highlights from each study? Let's start with ION-1 and ION-2.

Dr. Jensen: Historically, hepatitis C genotype 1 has been one of our more difficult-to-treat patient populations -- and 70% of the US population with hepatitis C has genotype 1 -- so most of the studies focused on interferon-free therapies for this genotype.

The ION studies use an interferon-free combination of sofosbuvir plus ledipasvir, with and without ribavirin. Sofosbuvir is a nucleotide inhibitor, and ledipasvir is an NS5A inhibitor. ION-1 and ION-2[1,2] compared 2 different regimens: ION-1 in treatment-naive patients, 16% of whom had cirrhosis, and ION-2 in treatment-experienced patients in whom a pegylated interferon and ribavirin-based therapy, with or without a protease inhibitor, had previously failed.

The regimens were similar in both of these ION studies. They compared 12 or 24 weeks of sofosbuvir and ledipasvir, with or without ribavirin. ION-1 had over 200 patients in each of the 4 arms, and ION-2 had over 100 patients in each of the 4 arms.

In ION-1, the SVR rate, or cure rate, for treatment-naive patients varied between 97% and 99%. These are truly remarkable cure rates in this patient population. In ION-2, patients in whom therapy had previously failed demonstrated SVR rates between 94% and 99%, which are almost as impressive as in ION-1.

ION-2 showed that it did not seem to matter whether patients had failed prior protease inhibitor treatment. Ribavirin really didn't add anything to the success of any of the arms in either of the 2 clinical trials.

The difference between 12 and 24 weeks was also not readily apparent. In the patients in ION-2, there was a slight numerical advantage at 24 weeks with 99%, but it was 94% and 96% in the 12-week arms.

A subanalysis of ION-2 examined treatment-experienced patients who had cirrhosis. Patients given sofosbuvir and ledipasvir with or without ribavirin for 12 weeks had a response rate of 82%-86%, whereas when they received it for 24 weeks, they did much better -- with an SVR of 100%. This will raise the issue of whether cirrhotic patients in whom previous therapy failed might do better with 24 weeks of treatment as opposed to just 12 weeks.

This was not a statistically significant difference, but certainly this point needs to be further assessed. The number of patients with cirrhosis in each of these arms is relatively small (only 22 patients in each arm), so maybe more robust numbers will give a better indication of whether a longer duration is needed in this patient population.

Medscape: What were some of the highlights from ION-3?

Dr. Jensen: ION-3[3] -- which was presented at this year's DDW meeting -- compared treatment durations of 8 weeks vs 12 weeks with a sofosbuvir and ledipasvir combination in treatment-naive, noncirrhotic patients with hepatitis C genotype 1. There were over 200 patients in each of the 3 arms: sofosbuvir and ledipasvir for 8 weeks; sofosbuvir, ledipasvir, and ribavirin for 8 weeks; and sofosbuvir and ledipasvir for 12 weeks. The SVR rate was between 93% and 95% in all of the arms. In the 8-week arms, it was 94% with sofosbuvir and ledipasvir and 93% with sofosbuvir, ledipasvir, and ribavirin; in the 12-week arm, it was 95% with sofosbuvir and ledipasvir.

This suggests that 8 weeks might be just as good as 12 weeks in treatment-naive patients with genotype 1. But a word of caution: There were no cirrhotic patients, and all were treatment-naive. There were no treatment-experienced participants.

So will 8 weeks become the standard, or is this an option only for some patients? Going forward, I think 8 weeks looks like it may be an option for treatment-naive patients with mild hepatitis C genotype 1, but it remains to be seen whether those with more complicated disease can benefit from a shorter treatment duration.

Medscape: Have shorter treatment durations, such as this one of 8 weeks, been looked at in other studies?

Dr. Jensen: An arm of the ELECTRON trial[4] investigated an even shorter duration -- 6 weeks of sofosbuvir and ledipasvir and ribavirin -- the thought being that if 8 weeks was as good as 12 weeks, what about 6 weeks? There were 25 patients in that arm, and they were treatment-naive and without cirrhosis. The SVR rate was only 68%.

So, it looks like you need more than 6 weeks, but 8 weeks looks like it's as good as 12 weeks. Eight weeks is probably the shortest duration that we can think about in treatment-naive patients with genotype 1 with this combination.

Medscape: Let's talk about some of the other studies. What are the highlights of SAPPHIRE and TURQUOISE?

Dr. Jensen: In SAPPHIRE and TURQUOISE, 3 direct-acting antiviral agents were combined with ribavirin. These agents were ABT450, which is a protease inhibitor and boosted with ritonavir; ABT267, which is an NS5A inhibitor now known as ombitasvir; and ABT333, which is a non-nucleoside inhibitor now known as dasabuvir.

SAPPHIRE I[5] included noncirrhotic patients with hepatitis C genotype 1 who had not been previously treated. They were treated with this so-called 3D combination plus ribavirin. An SVR rate of 96% was achieved in those treated for 12 weeks. So, again, this is very comparable to what we saw with the ION-1 study, but here there were no cirrhotic patients.

In SAPPHIRE II,[6] treatment-experienced noncirrhotic patients with hepatitis C genotype 1 were treated with 12 weeks of the 3D combination plus ribavirin, and they also achieved an SVR rate of 96%. There were 297 patients, which is a very robust number.

To answer the question of whether cirrhotic patients did differently, TURQUOISE II[7] was done in 380 patients with cirrhosis; both treatment-naive and treatment-experienced patients were included. One arm of 208 patients received 12 weeks of the 3D combination plus ribavirin, and in the other arm, 172 patients received 24 weeks of the 3D combination plus ribavirin. The SVR rate in the 12-week arm was 92%, and it was 96% in the 24-week arm. These are very good response rates in cirrhotic patients.

Medscape: Moving on to PEARL, these studies were undertaken to analyze genotype 1a and 1b separately. Could you share the highlights?

Dr. Jensen: There was a lingering question about whether genotype 1a and 1b respond similarly. Previous data from the SAPPHIRE studies had shown that genotype 1a responded a little less well than genotype 1b -- so, yes, the PEARL studies were undertaken to analyze genotype 1a and 1b separately.

PEARL III[8] included 419 patients with hepatitis C genotype 1b who were treatment-naive. They were given the 3D combination without ribavirin for 12 weeks, or the 3D combination with ribavirin for 12 weeks. It only studied a 12-week duration. The SVR rates were 99% in both arms, so it was extremely good in genotype 1b.

PEARL IV[8] examined genotype 1a, the subtype of genotype 1 that didn't respond quite as well as genotype 1b in prior studies. In this study, they had about 200 patients in the 3D combination without ribavirin and 100 patients in the 3D combination with ribavirin. The SVR rate was 90% in the 3D combination without ribavirin, and 97% in the 3D combination with ribavirin. So again, this is a high success rate -- a little less than PEARL III, but these were not head-to-head studies. What it suggests, however, is that patients do very well with this 3D combination with and without ribavirin. Genotype 1a may benefit a little more with ribavirin.

It's amazing that we're even saying that 90% is inferior, compared with where we were not that long ago. But this is where we're going with genotype 1, as you can see from all of the studies we discussed.

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