By Michael Smith, North American Correspondent, MedPage Today
Published: January 02, 2013
Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Investigational agents that act directly against the hepatitis C virus (HCV) may allow previously untreated patients to avoid interferon therapy, long a standard of care, researchers said.
Two phase IIa studies, reported in the Jan. 3 issue of the New England Journal of Medicine, found promising results with different agents, either without interferon or with reduced use of the drug.
Both studies also found less impressive outcomes among patients previously treated unsuccessfully with the standard combination of ribavirin and pegylated interferon.
The development of so-called direct-acting agents, delivered orally, has held the promise of eliminating the need for treatment with interferon, which is difficult to tolerate and must be administered by subcutaneous injection.
"The development of an interferon-free, all-oral treatment regimen would represent an important advance," argued researchers led by Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand.
In an open-label study, Gane and his colleagues gave the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for up to 12 weeks to eight groups of HCV patients:
- 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned, in groups of 10, to get the combination, with three groups also getting peginterferon alfa-2a for 4, 8, or 12 weeks, respectively
- two additional groups, each of 10 previously untreated patients also with genotypes 2 or 3, got sofosbuvir monotherapy for 12 weeks or sofosbuvir, peginterferon alfa-2a, and ribavirin for 8 weeks
- two groups of patients with HCV genotype 1 received sofosbuvir and ribavirin for 12 weeks -- 10 patients with no response to prior treatment and 25 with no previous treatment.
Gane and colleagues have previously reported some of the promising results in the genotype 2 and 3 patients but early outcomes among those with genotype 1, regarded as more difficult to cure, were disturbing.
Specifically, as they reported in the journal, 9 of 10 who had previously failed interferon-based treatment relapsed quickly after the end of treatment with sofosbuvir and ribavirin.
On the other hand, all of the patients in the first four groups achieved a sustained virologic response at 24 weeks (SVR24) – defined as no detectable HCV RNA 24 weeks after the end of therapy – which is usually regarded as a cure.
And all 10 patients who got sofosbuvir, peginterferon alfa-2a, and ribavirin for 8 weeks achieved SVR24, as did 6 of 10 who got sofosbuvir monotherapy.
Importantly, 21 of 25 previously untreated patients with HCV genotype 1 – or 84% -- achieved SVR24 after 12 weeks of treatment therapy with sofosbuvir and ribavirin.
Taken together, Gane and colleagues concluded, the data suggest that 12 weeks of the all-oral combination of sofosbuvir and ribavirin is likely to be effective regardless of genotype, as long as patients have not previously been treated with interferon and ribavirin.
The results "potentially pave the way" to an all-oral, short-duration regimen that does not use interferon, Gane and colleagues concluded, arguing that the combination of sofosbuvir and ribavirin deserves further study.
Investigators on the second study, led by Fred Poordad, MD, of the University of Texas Health Science Center in San Antonio, came to similar conclusions about a different regimen.
In a 12-week open-label study, a combination of two direct-acting agents, along with ribavirin, yielded good results in treatment-naïve patients with genotype 1 virus, but did less well among those who had previously been treated with interferon and ribavirin.
The investigational drugs were ABT-450, an inhibitor of the viral NS3 protease, boosted with low-dose ritonavir, and ABT-333, a non-nucleoside NS5B polymerase inhibitor.
All patients got ABT-333 and ribavirin, as well as one of two doses of ABT-450/r -- 250 or 150 mg daily, with 100 mg of ritonavir in either case – for 12 weeks and were followed for 48 weeks after the end of therapy.
The primary endpoint was the proportion of patients who reached a so-called extended rapid virologic response, defined as undetectable viral RNA from week 4 through week 12.
By that token, Poordad and colleagues reported:
- 17 of 19 treatment-naïve patients who got the high dose of ABT-450/r (89%) reached the primary endpoint
- Among treatment-naïve patients, 11 of 14 (79%) who got the lower dose achieved an extended rapid virologic response
- In those two groups, all patients who completed treatment had a sustained virologic response at 12 weeks after treatment -- 18 of the 19 in the first group and 13 of 14 in the second.
- In the third group of therapy-experienced patients, treatment with the low dose of ABT-450/r along with ABT-33 and ribavirin led to an initial decline of viral load in all patients.
- 10 of 17 patients (59%) had an extended rapid virologic response, six had virologic breakthrough during treatment, three had a relapse after treatment, and eight (47%) had a sustained virologic response 12 weeks after the end of therapy.
Poordad and colleagues argued that the findings suggest the regimen will do well among previously untreated patients with genotype 1 infection, but added that larger studies are needed to confirm the results.
The study by Gane and colleagues was supported by Pharmasset and Gilead Sciences.
Gane reported financial links with Roche, Pharmasset, Gilead, Novartis, Janssen-Cilag, Tibotec, and Boehringer Ingelheim.
The study by Poordad and colleagues was supported by Abbott.
Poordad reported financial links with Abbott, Vertex, Merck, Anadys Pharmaceuticals, Achillion, BMS, Gilead, Novartis, Genentech, Theravance, Onyx, Salix, Pharmasset, Idenix, Tibotec/Janssen, GlaxoSmithKline, Boehringer Ingelheim, and Pfizer.
Primary source: New England Journal of Medicine
Gane EJ, et al "Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C" N Engl J Med 2013; 368: 34-44.
Additional source: New England Journal of Medicine
Poordad F, et al "Exploratory study of oral combination antiviral therapy for hepatitis C" N Engl J Med 2013; 368 :45-53.