A four-drug combination of direct acting antivirals
developed by AbbVie cured hepatitis C infection in over 90% of participants in
the AVIATOR study, without the need for the use of interferon, researchers
reported at the International Liver Congress on Thursday in Amsterdam.
The results presented at the International Liver Congress
provided extended follow up on results first presented at the American Liver Meeting in November 2012.
The preliminary presentation to that meeting showed that
between 79% and 96% of previously untreated patients with genotype 1a HCV
infection achieved a sustained virologic response (an undetectable viral load
12 weeks after completing treatment, or SVR12), depending on the duration of
treatment and regimen to which they had been randomised. In previously untreated
patients with genotype 1b infection 96% - 100% of patients achieved SVR12. In
previously treated null responders 81-89% of genotype 1a patients and 100% of
genotype 1b patients achieved SVR12.
Glossary
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
- intent to treat analysis
All participants in a clinical trial are included in the final analysis, in the groups they were originally assigned to, whether or not they actually completed their course of treatment. Provides a better estimate of the real world effect of a treatment than an ‘on treatment analysis’.
At the International Liver Congress this week, Kris Kowdley of
Virginia Mason Medical Center, Seattle, presented 24-week post-treatment
follow-up data (SVR24) on 571 patients, showing very few cases of viral
breakthrough or relapse between weeks 12 and 24 post-treatment. Three patients experienced
relapse during this period, while a further eight have still to return for
follow up after week 12, and are counted as virologic failures in their
absence.
The AVIATOR study compared six different interferon-free
combinations of varying components or duration among previously untreated
patients and three different regimens among prior null responders. The aim was
to select future interferon-free combination regimens for testing in larger
phase III 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
Ninety-sex per cent of treatment-naïve patients and 93% of prior null
responders achieved SVR24. These results
come from the intent to treat analysis in which all patients who entered the
trial were counted, regardless of whether they completed the treatment course
or not. One case of virologic relapse occurred in a patient who received this
regimen, two weeks after completing treatment, and no cases of relapse occurred
after week 12 in patients receiving this regimen.
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-naïve and 88 null responders among the 571 patients. Among previously
untreated patients 98% of genotype 1b patients and 91% of genotype 1a patients
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 in treatment-naïve
patients. There was almost no difference in SVR24 rates by gender or by stage
of liver disease, but patients with baseline viral load below 7 log showed a
trend towards higher rates of cure among both treatment naïve (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, cirrhotic patients were not included in this
study. Therefore, it would be premature to draw conclusions about the efficacy
and safety of the study regimens in patients with the most advanced liver
disease.
Data on 80 patients treated for 24 weeks with the regimen of
ABT-450/r ABT-267, ABT-33 and ribavirin showed only a small difference in SVR24
rates when compared to 79 patients treated for 12 weeks with the same regimen. Ninety-three
per cent of treatment-naïve patients achieved SVR24 when treated for 24 weeks,
compared to 99% of patients treated for 12 weeks. Among null responders, 98% of
those treated with this regimen for 12 weeks achieved SVR24, compared to 93% of
those treated for 12 weeks.
Dr Kowdley told the conference: “The incremental gain of
treating from 12 to 24 weeks is small; 12 weeks of treatment seems quite satisfactory.”
Based on the results of the Aviator study AbbVie has
selected a 12-week regimen of all three investigational drugs plus ribavirin
for further study in phase III licensing trials.
Treatment was well tolerated by most patients; only 2.4% of
247 patients with available safety data discontinued treatment due to adverse
events, and four out of six discontinuations were judged to be due to the study
drugs. The most common side–effects were headache (31.2%), fatigue (29.6%) and
nausea (22.7%), but these were mild in most cases and did not lead to treatment
discontinuation.
No grade 3 or 4 cases of anaemia were observed. Six of 247
patients developed bilirubin elevations between three and ten times above the
upper limit of normal but these were not treatment-limiting, and all resolved
spontaneously.