Published: Jan 16, 2014
By Michael Smith, North American Correspondent, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
- Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3.
- The combination worked equally well with or without ribavirin.
Chronic hepatitis C (HCV) can be treated effectively without any of the standard drugs, researchers reported.
In an open-label study, all-oral combination therapy yielded cure rates ranging from 89% to 100% depending on patient and treatment characteristics, according to Mark Sulkowski, MD, of Johns Hopkins University, and colleagues.
Importantly, the combination of daclatasvir and sofosbuvir (Sovaldi)worked equally well with or without ribavirin, one of the mainstays of HCV therapy for years, Sulkowski and colleagues reported in the Jan. 16 issue of the New England Journal of Medicine.
The combination also worked equally well regardless of previous treatment failure, the presence of mutations associated with poor response to therapy, and viral genotypes regarded as difficult to treat, the investigators reported.
For years, chronic HCV was treated with pegylated interferon, an injectable drug with a host of difficult and dangerous side effects, and ribavirin, an oral drug with its own suite of hazards including hemolytic anemia and teratogenicity.
Therapy was usually protracted and cure rates -- sustained virologic responses (SVR), defined as no detectable HCV at a given point after the end of treatment -- were low.
The addition of drugs that block the HCV protease enzyme has improved outcomes, but clinicians and patients have been waiting for all-oral regimens that eliminate both interferon and ribavirin.
"In my view," Sulkowski told MedPage Today by email, "this clinical trial demonstrates the potential for interferon-free and ribavirin-free regimens for persons infected with HCV genotype 1."
In the trial, patients with genotypes 1, 2, or 3 of the virus were given daclatasvir/sofosbuvir, with or without ribavirin, for 12 or 24 weeks.
The primary endpoint -- reached by 201 of 211 patients -- was a sustained virologic response 12 weeks after the end of therapy, or SVR12.
SVR12 rates were:
- 98% in previously untreated genotype 1 patients and the same in genotype 1 patients who had failed previous therapy with interferon, ribavirin, and HCV protease inhibitors
- 92% of patients with genotype 2, and 89% of those with genotype 3 infection
- 98% and 100%, respectively, among patients with HCV subtypes 1a and 1b
- 93% and 98%, respectively, for those with CC and non-CC IL28B genotypes, where the non-CC genotypes are regarded as predicting poor response
- 94% among those who also got ribavirin, and 98% among those who did not
The study heralds an "exciting time for HCV treating physicians," commented Paul Pockros, MD, of the Scripps Clinic in La Jolla, Calif., who was not part of the study.
"We can cure most patients finally," he told MedPage Today by email.
Whether those cures will come from the daclatasvir/sofosbuvir combination, however, is an open question.
As data from this trial was revealed at successive medical meetings, Pockros and others hailed the outcomes as a "home run" for HCV treatment.
Fears for the Future
But there were fears it would be a strikeout for patients -- the two drugs are owned by different companies and were being tested under a collaborative agreement that has now ended.
Among other things, that means the drugs are unlikely to be co-formulated as a single pill or approved as a combination with a broad indication.
But Sulkowski noted that three phase III trials have been registered, although they are not yet recruiting, for relatively narrow indications -- genotype 3 patients, those with concurrent HIV, and people with cirrhosis or recurrent HCV after liver transplant.
The two drugs are so-called direct-acting anti-virals -- they target aspects of the virus itself, rather than boosting the immune system as interferon does.
Daclatasvir blocks the action of the viral NS5A replication complex, while sofosbuvir, approved last year, is a nucleotide analog NS5B polymerase inhibitor.
Gilead is testing the combination of sofosbuvir and ledipasvir, its own NS5A inhibitor. BMS is testing triple therapy with daclatasvir, an NS5B blocker dubbed BMS-791325, and asunaprevir, a protease inhibitor.
But if daclatasvir is approved on its own, Pockros said, it's likely some doctors at least will prescribe it with sofosbuvir off label.
Indeed, the two most recently approved HCV drugs are sofosbuvir and the protease inhibitor simeprevir (Olysio) -- neither indicated for use with the other.
But, Pockros said, they are being widely used together based on data from a clinical trial that has been reported but not yet published.
"Support for the (daclatasvir/sofosbuvir) regimen will be even firmer," he said, although it's not clear how gladly insurers would support such use.
A Practice-Changing Regimen?
The bottom line, Sulkowski said, is that the study suggests that the combination -- or one using similar medications -- has the potential to make an important impact on HCV therapy.
"The combination of an NS5A inhibitor and an NS5B inhibitor was associated with high cure rates in a range of HCV-infected patients," he and colleagues argued.
A separate open-label phase 2b study in the journal evaluated triple or quadruple drug regimens given for eight, 12, or 24 weeks in a cohort of 571 patients divided into 14 treatment subgroups.
The research groups overlapped -- Sulkowski, for instance, was part of both studies -- but with the exception of ribavirin, none of the drugs, all direct-acting anti-virals, were the same.
The primary analysis was the rate of SVR24 among treatment-naive patients who got three direct-acting agents plus ribavirin for eight weeks, compared with those who got the same therapy for 12 weeks, according to Kris Kowdley, MD, of Virginia Mason Medical Center in Seattle, and colleagues.
Kowdley and colleagues studied the HCV protease inhibitor ABT-450 boosted with ritonavir, the non-nucleoside polymerase inhibitor ABT-333, the NS5A inhibitor ABT-267, and ribavirin in patients with genotype 1 infection.
The key finding, they reported, was that 88% of those who got eight weeks of therapy and 95% of those who got 12 weeks reached an SVR24.
The seven percentage-point difference was not statistically significant, the researchers reported.
Over all treatment groups, SVR24 rates ranged from 83% to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia.
The study by Sulkowksi and colleagues was supported by Bristol-Myers Squibb and Pharmasset (Gilead). Sulkowski reported financial links with the companies, as well as Novartis, Janssen, Vertex, BIPI, Abbott, Merck, Roche/Genentech, BIPI, and Pfizer.
The study by Kowdley and colleagues was supported by AbbVie. Kowdley reported financial links with the company, as well as with Boehringer Ingelheim, BMS, Gilead/Pharmasset, Intercept, Janssen, Merck, Mochida, Vertex, and Novartis.
Pockros has reported financial links with Novartis, Tibotec, GlobeImmune, Genentech, Merck, BMS, Gilead, Vertex, Three Rivers Pharmaceuticals, Debio, Pfizer, Conatus Pharmaceuticals, Abbott, and Mochida Pharmaceuticals.
Primary source: New England Journal of Medicine
Source reference: Sulkowski MS, et al "Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection" N Engl J Med 2014; 370: 211-221.
Additional source: New England Journal of Medicine
Source reference:Kowdley KV, et al "Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1" N Engl J Med 2014; 370: 222-232.