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Interferon-free hepatitis C treatment safe, proves effective in up to 63% of patients with cirrhosis
Keith Alcorn, 2012-11-15 18:30:00
The first major data on interferon-free hepatitis C treatment in people with cirrhosis shows that treatment can be safe, and proved effective in up to 63% of patients, according to results from the SOUND-C2 study presented this week at the 63rd meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.
Despite their higher risk of progression to decompensated cirrhosis and liver cancer, most earlier-stage research studies of new hepatitis C drugs exclude people with more severe liver damage on the grounds of safety and the unpredictable processing of drugs by a more damaged liver. Moreover, because response rates tend to be poorer in this population, which would make the drug appear to perform poorly in comparison with competitor products, companies are unlikely to risk harming early perceptions of products by recruiting cirrhotic patients into general phase II trials.
Paradoxically it is likely to be patients with cirrhosis and advanced liver disease that will be given priority for treatment with new agents as they become available. Data from earlier stage studies are likely to give people with more advanced disease an earlier indication of whether the chance of curing hepatitis C infection will be greatly improved if they defer hepatitis C treatment until new drugs are available.
The SOUND-C2 study was a phase IIb safety and efficacy study comparing the performance of interferon-free combinations of an HCV protease inhibitor faldaprevir(BI-201335) and a non-nucleoside NS5b inhibitor (BI-207127) with or without ribavirin. These directly-acting antivirals are being developed by Boehringer Ingelheim.
Participants were randomised into five study arms:
- faldaprevir 1335mg once daily + BI-207127 600mg three times daily + ribavirin for 16 weeks, for 28 weeks or 40 weeks
- faldaprevir 1335mg once daily + BI-207127 600mg twice daily + ribavirin for 28 weeks
- faldaprevir 1335mg once daily + BI-207127 600mg three times daily
A total of 362 patients, 37 with liver cirrhosis, were recruited to this open-label, phase 2b study. Participants with cirrhosis were not distributed equally across the study arms, and the number of patients in the study with cirrhosis was also small, limiting the power of the study to provide any evidence regarding the relative performance of different regimens in patients with compensated cirrhosis.
Nevertheless, noted Dr Vicente Soriano of Hospital Carlos III, Madrid, presenting the results, this is the first trial to report data on the performance of interferon-free regimens in patients with compensated cirrhosis.
Overall, these interferon-free combinations achieved good results. Some 84% of patients with genotype 1a infection and the IL28B gene had a sustained virological response (SVR) at week twelve. In a separate presentation, Dr Stefan Zeuzem of the Klinikum der J.W. Goethe-Universitat, Frankfurt, presented final overall 24-week (SVR24) results of the SOUND-C2 study, showing SVR12 rates of between 52% and 69% in the ribavirin-containing arms and 39% in the ribavirin-sparing arm.
Across the study population as a whole three baseline characteristics were strongly predictive of a sustained virological response: HCV genotype 1b (adjusted odds ratio 7.11), IL2bB `CC` host genotype (AOR 4.94) and female (AOR 3.94) (all p <0.0001).
When results were stratified according to HCV sub-genotype the best results were seen in genotype 1b patients who received BI-207127 twice daily for 28 weeks (85% achieved SVR12), and this dose will now be taken forward for further study in phase III licensing studies. However Dr Zeuzem noted that a treatment duration of greater than 16 weeks did not substantially improve outcomes in patients with HCV genotype 1b.
In genotype 1a patients, by comparison, between 38% and 47% achieved SVR12 according to the dosing regimen. These results reflect the greater potency of both drugs against genotype 1b, Dr Zeuzem commented.
There was also a trend towards better outcomes in patients with the IL28B `CC` host genotype, which predicts a better response to interferon-based therapy. Eighty-four per cent of patients with the `CC` genotype achieved SVR12 in the twice-daily treatment group, compared to 64% of patients with a non-CC genotype.
In patients with cirrhosis SVR12 rates ranged between 29% and 63% for patients taking ribavirin-containing regimens. Responses were better in patients with the IL28B `CC` gene compared to those who lacked this mutation. Once again, the best outcomes were seen in those with the IL28B `CC` host genotype who were treated with once-daily faldaprevir combined with twice-daily BI 207127 and weight-based ribavirin (63% SVR12).
Response rates in non-cirrhotic patients ranged from 29% to 88%. Once again, the IL28B CC gene was associated with better outcomes, especially in those treated with the BI 201335/BI 207127/ribavirin combination.
Irrespective of cirrhosis status, none of the patients who lacked the IL28B `CC` genotype who were taking dual therapy faldaprevir /BI 207127 achieved a sustained virologic response. This compared to a response rate of between 33% and 55% in those with this gene.
The most common side-effects in patients with cirrhosis were mild rash and gastrointestinal complaints. Overall, 8% of participants discontinued treatment due to serious adverse events, most of which were not judged to be drug-related.
The investigators emphasised the good response rate seen in patients with cirrhosis treated with faldaprevir /BI 207127/ribavirin, as well as the favourable tolerability profile of this combination in this patient group. The combination will continue to be investigated in phase 3 trials involving patients with cirrhosis.
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