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April 23rd, 2013
Two Papers, Four Sofosbuvir Studies, and Soon the End of “Interferonologists”
Today, as the The International Liver Congress is about to start, two papers are published in the New England Journal of Medicine on sofosbuvir, the investigational anti-HCV nucleotide submitted to the FDA for approval earlier this month.
Each paper actually includes within them two studies. (For some reason, all the studies sound like 1950s science fiction magazines.) Typical of the frenetic pace of drug development for HCV, the trial designs are a byzantine mish-mash of study populations, strategies, and endpoints, which can make interpretation complex. As a result, here’s an attempt to summarize some key outcomes, with a focus on the bottom line — cure — making the not-so-bold leap that “sustained virologic response at 12 weeks” = “cure”.
One paper looked at treatment-naive patients with any HCV genotype, and included the NEUTRINO and FISSION studies. NEUTRINO was a single-arm treatment with peg IF, RBV and sofosbuvir for genotypes 1, 4, 5, and 6, and FISSION a randomized comparison between sofosbuvir and interferon (both with RBV) for genotypes 2 and 3:
- NEUTRINO: Genotype 1, 12 weeks of peg IF + RBV + sofosbuvir: 89% cure
- NEUTRINO: Genotype 4, 12 weeks of peg IF + RBV + sofosbuvir: 96% cure (Note: very few genotype 5 or 6 patients)
- FISSION: Genotype 2, 12 weeks of RBV + sofosbuvir: 97% cure
- FISSION: Genotype 3, 12 weeks of RBV + sofosbuvir: 56% cure
In the randomized comparison for the genotype 2/3 patients, response rates were similar between sofosbuvir for 12 weeks and interferon for 24 weeks (both with RBV); the sofosbuvir strategy was better tolerated. No resistance to sofosbuvir was detected in any patient.
The other paper — remember, also with two studies — looked only at patients with genotype 2 or 3 HCV, and in whom “peginterferon is not an option”. In one study (POSITRON), this could be for multiple reasons, such as prior adverse effects, concurrent medical conditions, or just refusing interferon; they were randomized to RBV + either sofosbuvir or placebo for 12 weeks. In the other study (FUSION), these were patients who did not respond to prior treatment with interferon, randomized this time to 12 or 16 weeks of RBV + sofosbuvir. Again, some cure rates (all genotype 2 or 3):
- POSITRON: Interferon not an option, 12 weeks RBV + sofosbuvir: 78% cure
- POSITRON: Interferon not an option, 12 weeks RBV + placebo: 0% cure (Note: must have included this for safety reasons, right?)
- FUSION: Prior non-response to interferon, 12 weeks RBV + sofosbuvir: 50% cure
- FUSION: Prior non-response to interferon, 16 weeks RBV + sofosbuvir: 73% cure
Patients with cirrhosis and/or genotype 3 didn’t do as well — extending the treatment to 16 weeks seemed to increase cure rates
No doubt these are terrific results, suggesting that sofosbuvir-based therapy will be both more effective and better tolerated than current standard of care. And also no doubt this week’s “Liver Congress” will have further interferon-sparing studies for HCV that could make these published studies seem out of date, even before the sofosbuvir is approved.
Nonetheless, as of right now — April 23, 2013, 2:43 PM EST — as an editorialist appropriately notes, it’s not quite time to say farewell to the “Interferonologists” among us who spend the bulk of HCV treatment time managing side effects.
The good news is that time is undoubtedly coming soon.