Miriam E. Tucker

April 12, 2014

LONDON — An interferon-free triple-combination antiviral regimen was nearly universally effective in treating patients infected with hepatitis C genotype 1 in 2 new phase 3 trials.

AbbVie's combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir, and the nonnucleoside polymerase inhibitor dasabuvir and ribavirin produced 96% sustained viral response rates at 12 weeks among previously treated and treatment-naive patients infected with hepatitis C genotype 1. The so-called "3D" regimen was well tolerated in both trials.

"This was a very, very effective treatment regimen," said Alessio Aghemo, MD, director of the hepatology outpatients clinic in the 1st Gastroenterology Unit at the Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, at the University of Milan, in Italy.

The results were presented here at the European Association for the Study of the Liver International Liver Congress 2014 and published simultaneously online in the New England Journal of Medicine.


The retreatment study, SAPPHIRE II, was presented by Stefan Zeuzem, MD, of Johann Wolfgang Goethe University, in Frankfurt, Germany, and published online on April 10.

This double-blind placebo-controlled trial enrolled 394 patients with noncirrhotic hepatitis C genotype 1 who had previously been treated with peginterferon-ribavarin and had relapsed, partially responded, or not responded. They were randomly assigned in a ratio of 3:1 to receive either the 3D combination or matching placebo for a 12-week double-blind period, which was followed by an open-label treatment period of up to 24 weeks.

The overall intent-to-treat 12-week sustained virologic response (SVR12) was 96.3% (286/297), with no significant difference between genotype 1a (96.0%; 166/173) and genotype 1b (119/123; 96.7%). High SVR12 rates were also seen for all groups that had previously received peginterferon/ribavirin: 95.3% (82/86) in previous relapsers, 100% (65/65) in previous partial responders, and 95.2% (139/146) in previous null responders, Dr. Zeuzem reported.

Adverse events were more common with the 3D combination than with placebo (91.2% vs 82.5%; P < .05). This was primarily due to higher rates of pruritis (13.8% vs 5.2%). The adverse events were "generally mild and manageable," said Dr. Zeuzem, and only 1.0% of the study patients discontinued treatment because of adverse events.


The study of treatment-naive patients, SAPPHIRE I, was presented by Jordan Feld, MD, from the University of Toronto, and published online on April 11.

The study design for SAPPHIRE I was similar to that of SAPPHIRE II, but enrolled 631 patients with noncirrhotic hepatitis C genotype 1 who had not previously been treated.

The overall intent-to-treat SVR12 rate was 96.2%, with equally high SVR12 responses for genotype 1a (95.3%, 307/322) and 1b (98.0%, 148/151). On-treatment failure and post-treatment relapse rates were low, at 0.2% (1/473) and 1.5% (7/463), respectively, Dr. Feld reported.

Overall adverse events were more common with treatment than with placebo (87.5% vs 73.4%; P < .001). Nausea, pruritis, insomnia, diarrhea, and asthenia were all more common in patients receiving the 3D regimen (P < .05 for all). However, adverse events were mild in most patients; there were low rates of study discontinuation related to these events (0.6%), and low rates of serious adverse events (2.1%).

Dr. Aghemo, who was not involved in the trials, told Medscape Medical News that the AbbVie 3D regimen is given as twice-daily pills, which makes it slightly more cumbersome than Gilead's once-daily fixed-dose combination of sofosbuvir and ledipasvir, another direct-acting antiviral combination hepatitis C treatment. And, in some instances, the Gilead combination can be used for a shorter period. Phase 3 data for this combination are also being presented at the conference.

"In terms of efficacy, all these regimens are incredible. In terms of safety, there are no problems whatsoever with any of them. They're perfect," said Dr. Aghemo.

"We won’t have [head-to-head] comparison data, so probably cost will drive the choice," he added.

With hepatitis C direct-acting antiviral combinations from Merck and Bristol-Myers Squibb coming down the line soon, the costs are likely to drop rapidly, he said. "In countries where you have an insurance-based health system like the US, prices will go down in 12 to 18 months," Dr. Aghemo predicted.

Both SAPPHIRE studies were funded by AbbVie. Dr. Aghemo has received speaker fees from Gilead Sciences, AbbVie, Janssen, Merck, and Roche. Dr. Zeuzem reports personal fees from AbbVie during the conduct of the study, and personal fees from Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Roche, Santaris, and Vertex outside the submitted work. Dr. Feld reports receiving consulting fees from Boehringer Ingelheim, Gilead Sciences, Vertex Pharmaceuticals, Achillion Pharmaceuticals, Bristol-Myers Squibb, Idenix Pharmaceuticals, Janssen Pharmaceuticals, and Merck; and grant support from Roche, Boehringer Ingelheim, Gilead Sciences, Santaris Pharma, and Vertex Pharmaceuticals.

European Association for the Study of the Liver (EASL) International Liver Congress 2014: Abstracts 01 and 060. Presented April 10 and April 11, 2014.


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