- Category: HCV Treatment
- Published on Friday, 26 April 2013 00:00
- Written by Keith Alcorn
A 4-drug combination of direct-acting antivirals developed by AbbVie cured genotype 1 hepatitis C virus (HCV) infection in over 90% of participants in the AVIATOR study, without the need for the use of interferon, researchers reported at the 48th International Liver Congress (EASL 2013) on Thursday in Amsterdam. A 12-week treatment course will go forward to Phase 3 studies.
The results provided extended follow up on results first presented at the AASLD Liver Meeting in November 2012 and the 2013 Conference on Retroviruses and Opportunistic Infections this past March.
The Aviator study was designed to compare 6 different interferon-free combinations of varying components or duration among previously untreated patients without cirrhosis, and 3 different regimens among prior null responders, with the aim of selecting future interferon-free combination regimens for testing in larger Phase 3 studies.
The study compared combinations of:
- The once-daily HCV protease inhibitor ABT-450, boosted by ritonavir;
- The once-daily HCV NS5A inhibitor ABT-267;
- The twice-daily HCV non-nucleoside polymerase inhibitor ABT-333;
The preliminary presentation to the AASLD meeting showed that between 79% and 96% of previously untreated patients with genotype 1a HCV infection treated for 12 weeks achieved a sustained virological response, or undetectable viral load 12 weeks after completing treatment (SVR12), depending on the duration of treatment and the regimen to which they had been randomized.
In previously untreated patients with easier-to-treat genotype 1b infection, 96% to 100% of patients achieved SVR12. In previously treated null responders, 81% to 89% of genotype 1a patients and 100% of genotype 1b patients achieved SVR12.
At the International Liver Congress this week, Kris Kowdley of Virginia Mason Medical Center in Seattle presented 24-week post-treatment follow-up (SVR24) data for 571 patients, including 80 treatment-naive participants and 43 null responders treated for 24 weeks.
There were very few cases of viral breakthrough or relapse between weeks 12 and 24 post-treatment. Kowdley reported that 3 patients experienced relapse during this period, while a further 8 have still to return for follow-up after week 12, and are counted as virological failures in their absence.
Focusing on 247 patients who received all 4 drugs, by intent-to-treat analysis in which all patients were counted, regardless of whether they completed the treatment course or not, 96% of treatment-naive patients and 93% of prior null responders treated for 12 weeks achieved SVR24, as did 90% of treatment-naive patients and 95% of prior null responders treated for 24 weeks.
A single case of virological relapse occurred in a patient who received the 12-week regimen, 2 weeks after completing treatment, but no cases of relapse occurred after week 12.
As at week 12 post-treatment, there was no substantial difference between previously untreated patients and prior null responders in their response to therapy. SVR24 results by sub-genotype were available for 158 treatment-naive and 88 null responders among the 247 patients, showing that 98% of genotype 1b patients and 91% of genotype 1a patients receiving quadruple therapy achieved SVR24. Among previous null responders, 97% of genotype 1b and 93% of genotype 1a patients achieved SVR24.
Sub-genotype was the baseline characteristic which had the most pronounced impact on the likelihood of achieving SVR24 among treatment-naive patients. There was almost no difference in SVR24 rates by gender, IL28B status or stage of liver disease (although people with cirrhosis were excluded), but patients with baseline viral load below 7 log showed a trend towards higher rates of cure among both treatment naive (94% vs 89%) and prior null responders (96% vs 91%).
However, any differences according to baseline characteristics need to be treated with caution because in the cases of baseline viral load and IL28B status, the numbers of patients available for comparison are small. Similarly, the exclusion of cirrhotic patients from this study makes it premature to draw conclusions about the efficacy and safety of the study regimens in patients with the most advanced liver disease.
There was no substantive difference in SVR24 rates when comparing 12 vs 24 weeks of treatment with the quadruple regimen.
Kowdley told the conference: "The incremental gain of treating from 12 to 24 weeks is small; 12 weeks of treatment seems quite satisfactory."
Treatment was well tolerated by most patients; only 2.4% of 247 patients on the 4-drug regimen discontinued treatment due to adverse events, and 4 out of 6 discontinuations were judged to be due to the study drugs. The most common side effects were headache (31%), fatigue (30%) and nausea (23%), but these were mild in most cases and did not lead to treatment discontinuation.
No grade 3 or 4 cases of anemia were observed. Although 6 of 247 patients developed bilirubin elevations between 3 and 10 times above the upper limit of normal, these were not treatment-limiting, and all resolved spontaneously.
Based on the results of the Aviator study AbbVie has selected a 12-week regimen of all 3 investigational drugs plus ribavirin for further study in Phase licensing trials.
KV Kowdley, E Lawitz, F Poordad, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267 and ABT-33 +/- ribavirin in patients with chronic genotype 1 infection: results from the Aviator study. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 3.
AbbVie. New Data from AbbVie’s Phase IIb Aviator Trial Demonstrate High Sustained Viral Response Rates Across Multiple Patient Types with HCV Genotype 1. Press release. April 23, 2013.