An interferon-free regimen of daclatasvir plus sofosbuvir, with or without ribavirin, cured all previously treated hepatitis C (HCV) patients who did not respond to interferon-based triple therapy using the approved HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivo or Incivek), according to a report on Saturday at the 48th International Liver Congress (EASL 2013) in Amsterdam.
The advent of direct-acting antivirals has changed the treatment paradigm for chronic hepatitis C. Yet many people with progressive liver disease are not in a position to wait for all-oral regimens, and no options have been proven effective for people who experience treatment failure on the latest standard-of-care regimen consisting of pegylated interferon, ribavirin and one of the approved HCV NS3 protease inhibitors, boceprevir or telaprevir.
Mark Sulkowski from Johns Hopkins University and colleagues conducted a proof-of-concept study to evaluate an all-oral regimen containing Bristol-Myers Squibb's NS5A replication complex inhibitor daclatasvir (formerly BMS-790052) plus Gilead Sciences' nucleotide analogue HCV polymerase inhibitor sofosbuvir (formerly GS-7977), with or without ribavirin, for people who experienced treatment failure with boceprevir or telaprevir.
As Dr Sulkowski previously reported at The Liver Meeting in November 2012, the daclatasvir/sofosbuvir combination was shown to be highly effective, demonstrating near complete sustained virological response for previously untreated patients.
The current study enrolled 41 people with genotype 1 chronic hepatitis C, more than 80% of whom had harder-to-treat subtype 1a. Nearly two-thirds were men, 90% were white and the median age was 58 years (older than the population in most hepatitis C trials). People with known liver cirrhosis were excluded from the study, but more than 80% had estimated Metavir scores of F2 (moderate fibrosis) or higher according to non-invasive tests. Almost all had unfavourable (CT or TT) IL28B gene patterns.
Most (about 80%) had previously used telaprevir, while about 20% had used boceprevir. Participants were roughly evenly divided between prior non-responders (continued detectable HCV RNA at the end of treatment), prior viral breakthroughs on treatment, and prior relapsers. Those who had stopped boceprevir or telaprevir due to adverse events were excluded. Nearly half still had boceprevir or telaprevir resistance mutations, even though the median time since last treatment was four years.
Study participants were randomly assigned to receive 60mg once-daily daclatasvir plus 400mg once-daily sofosbuvir, either as a dual regimen or with 1000-1200mg/day weight-based ribavirin, for 24 weeks.
Viral decline was robust and rapid, with all participants on dual therapy and all but one on triple therapy reaching undetectable viral load by treatment week 4. The rate of viral decline did not differ according to pre-existing resistance mutations. End-of-treatment response rates at the end of 24 week were 100% for both groups. All participants had sustained virological response (SVR) at 4 weeks post-treatment (SVR4).
At 12 weeks post-treatment, SVR12rates were 100% in the sofosbuvir/daclatasvir arm and 95% in the sofosbuvir/daclatasvir/ribavirin arm. Dr Sulkowski explained, however, that the one patient who did not show up for the 12-week post-treatment visit – and was counted as a non-responder in the intent-to-treat (missing = failure) analysis – came back for the 24-week post-treatment visit and still had undetectable HCV. Therefore, SVR24 rates were 100% in both arms. No virological failures or relapses occurred.
Treatment was generally safe and well tolerated in both groups. There was a single serious adverse event in the triple-therapy arm, but no discontinuations for this reason. Side-effects were generally similar in both groups. People receiving ribavirin reported more fatigue and gastrointestinal symptoms, but none developed serious anaemia.
The researchers concluded that the all-oral, once-daily combination of daclatasvir plus sofosbuvir with or without ribavirin achieved SVR in all HCV genotype 1 patients who had experienced prior treatment failure with boceprevir or telaprevir and pegylated interferon/ribavirin.
"Neither baseline NS3 protease inhibitor resistance variants nor use of ribavirin influenced response," they continued. "These data provide proof-of-concept that the combination of two potent direct-acting antivirals with different viral targets is effective in patients who failed [pegylated interferon/ribavirin] plus a protease inhibitor."
"We can tell our patients who failed triple therapy they now appear to have a path forward toward a cure," Dr Sulkowski said.
Sulkowski MS et al. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naive GT2/3 HCV-infected patients (FISSION). 48th International Liver Congress (EASL 2013), abstract 1417, Amsterdam, 2013.