By Michael Smith, North American Correspondent, MedPage Today
Published: January 18, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
A combination of direct-acting antiviral agents aimed at hepatitis C -- and given without standard therapy -- can lead to sustained virologic response in patients with a difficult-to-treat strain of the virus.
In an "exploratory" phase II study, four of 11 patients treated with the two agents daclatasvir and asunaprevir had undetectable levels of the virus 12 and 24 weeks after the end of treatment, according to Anna Lok, MD, of the University of Michigan Ann Arbor, and colleagues.
All of the patients had previously failed standard therapy with pegylated interferon and ribavirin, Lok and colleagues reported in the Jan. 19 issue of the New England Journal of Medicine.
The finding is a "proof-of-concept" that combining agents that directly target the virus through different mechanisms can yield good outcomes even without the standard therapy, the researchers argued.
On the other hand, results were even better in the second arm of the study, in which 10 patients were given all four drugs: all had a sustained virologic response 12 weeks after stopping treatment and nine still had undetectable levels of hepatitis C RNA after 24 weeks.
Sustained virologic response – defined as a plasma level of viral RNA of less than 10 IU per milliliter 12 weeks after treatment ends – is regarded as the functional equivalent of a cure, since the virus rarely rebounds after that.
In clinical trials, standard therapy with pegylated interferon and ribavirin yields sustained virologic responses in no more than half of patients with the difficult to treat genotype 1 and in no more than 80% of those with genotypes 2 or 3.
But regimens including pegylated interferon and ribavirin are difficult to take and real-world effectiveness is much lower, leading to a growing interest in other agents that attack viral replication directly and may be used without interferon and ribavirin.
That's why the current study is a "watershed moment" in hepatitis C therapy, according to Raymond Chung, MD, of Massachusetts General Hospital in Boston.
In an accompanying editorial, Chung said that researchers can "certainly" do even better than Lok and colleagues by adding other direct-acting agents into the mix.
With other classes in development – such as nucleotide polymerase inhibitors – "we are on the threshold of a treatment revolution," Chung argued.
"There has never been a more exciting time for patients and providers who grapple with this silent killer," he concluded.
The two drugs under study both attack the viruses' ability to replicate inside cells. Daclatasvir inhibits the NS5A replication complex, while asunaprevir blocks the activity of the NS3 protease enzyme.
For this study, Lok and colleagues enrolled 21 patients with genotype one hepatitis C who had not responded to previous therapy and assigned them randomly to get the two drugs alone or in combination with standard therapy for 24 weeks.
The primary endpoint was a sustained virologic response 12 weeks after therapy ended.
Lok and colleagues reported:
- Four patients in the two-drug group (36%) met the primary endpoint, including two of the nine with viral genotype 1a and both of those with genotype 1b.
- Six patients -- all with genotype 1a -- had viral breakthrough while receiving therapy, and in all of them the researchers found resistance mutations to both antiviral agents.
- All 10 patients in the four-drug group had a sustained virologic response 12 weeks after treatment, and nine maintained that for another 12 weeks.
The most common adverse event in both groups was diarrhea, and six patients had transient elevations of alanine aminotransferase levels to more than three times the upper limit of the normal range.
The study is not the first to find such a result; Japanese researchers have also shown that the two drugs in combination – but without interferon -- can lead to promising outcomes.
But in that open-label, single-arm study, all the patients had genotype 1b virus, which appears to respond better to therapy than genotype 1a.
The study was supported by Bristol-Myers Squibb.
Lok reported financial links with Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck–Schering-Plough, and Roche. Other authors also reported financial links with industry and several are either employees of or hold stock in Bristol-Myers Squibb.
Chung reported financial links with Merck, Gilead, Pfizer, Roche, and Schering.
Primary source: New England Journal of Medicine
Lok AS, et al "Preliminary study of two antiviral agents for hepatitis C genotype 1" N Engl J Med 2012; 366: 216-224.
Additional source: New England Journal of Medicine
Chung RT "A watershed moment in the treatment of hepatitis C" N Engl J Med 2012; 366: 273-275.