November 7, 2013
A report released this week is adding to growing expectations that it may soon be possible to cure even the toughest cases of hepatitis C without months of weekly injections that cause nasty side effects.
The report, published yesterday in The Lancet, says a daily pill containing the novel drugs sofosbuvir and ledipasvir cleared the virus from 97 of 100 hepatitis C patients after 12 weeks in a phase 2 trial.
All of the patients were infected with hepatitis C virus (HCV) genotype 1, the most common strain in the United States and one of the hardest to treat. Forty of the patients had not responded to previous established HCV treatments. Some patients also had cirrhosis due to their infection.
“To our knowledge, this trial is the first to report data for cirrhotic genotype-1 patients who had not responded to prior treatment with a protease inhibitor regimen, a population without treatment options at present,” the authors write. “Our data lend support to the possibility of effectively treating all patients with genotype-1 HCV with a brief, all-oral, once-daily regimen that has no known safety issues.”
One of the two drugs, sofosbuvir, is expected to gain approval by the Food and Drug Administration (FDA) in December, according to a recent Associated Press report. On the negative side, however, there are indications that it and similar agents that may reach the market soon are likely to be extremely expensive.
Sofosbuvir is described as an HCV NS5B polymerase inhibitor, while ledipasvir is an NS5A inhibitor.
Limitations of existing treatment
The Centers for Disease Control and Prevention (CDC) estimates that 3.2 million people in the United States have HCV infection. The current standard treatment for it now involves weekly injections of interferon-alpha with ribavirin, plus a protease-inhibitor for those with genotype 1. The treatments typically continue for 24 to 48 weeks.
The standard treatment is reported to be effective in more than two thirds of HCV patients. But as noted by the authors, interferon causes serious side effects, such as muscle pain, flulike symptoms, and depression, and the treatment is medically contraindicated for many. In addition, protease inhibitors can exacerbate the side effects of interferon.
The new trial was conducted by researchers from the Texas Liver Institute and University of Texas Health Science Center in San Antonio and from Gilead Sciences Inc., Foster City, Calif. The company developed both drugs and sponsored the trial, whose lead author is Eric Lawitz, MD, of the Texas Liver Institute.
The researchers recruited 100 adult HCV genotype 1 patients for the trial. Of those, 60 had had no previous treatment, while the other 40 had received interferon with ribavirin and a protease inhibitor but did not respond or suffered a relapse. Of those 40, 22 had cirrhosis.
The previously untreated patients were randomly assigned to receive only the sofosbuvir-ledipasvir combination for 8 weeks or 12 weeks or sofosbuvir-ledipasvir plus ribavirin for 8 weeks. The previously treated group received 12 weeks of treatment with sofosbuvir-ledipasvir alone or the dual drug plus ribavirin.
The regimen yielded a “sustained virologic response” (SVR)—elimination of the virus—in 97 of the 100 patients, the report says. The SVR rate was at least 95% in each of the five treatment groups. Two patients had a viral relapse, and one patient was free of the virus at 8 weeks but was then lost to follow-up.
Good safety profile
On the safety side, 48 of the 100 patients had at least one adverse event during the trial, though none dropped out as a result. The most common adverse events were nausea, anemia, upper respiratory tract infection, and headache; treating physicians rated most of these as mild. The only serious adverse event that was considered related to the treatment was anemia with suicidal ideation. Anemia was seen only in patients given ribavirin.
The authors write that patients with characteristics that have typically predicted a poor response to interferon-based treatment, including a resistant strain of HCV, black race, and a high baseline viral load, had 12-week viral clearance rates similar to those without such characteristics.
“The results of this trial suggest that the fixed-dose combination of sofosbuvir and ledipasvir could offer a short, all-oral treatment that is effective in treatment-naive and previously treated patients,” the researchers say.
In an accompanying editorial, two Australian experts, Margaret E. Hellard, MBBS, PhD, and Joseph S. Doyle, MBBS, MSc, welcome the findings but say they need to be confirmed by larger trials, which are now under way. They work at the Burnet Institute, the Alfred Hospital, and Monash University, all in Melbourne.
If the findings are further confirmed, “then this treatment would not only substantially improve virological response to HCV genotype 1, but the mode of HCV treatment delivery could substantially shift away from hospital based to community settings,” they write.
“However, this was a small, single-centre study with short follow-up, raising concerns about the representativeness of the sample and generalisation to real-world settings. The full implications of these results need to be tempered for now.”
Hellard and Doyle comment that the approach of the “era of highly effective interferon-free treatment” for HCV raises several difficult questions. One is whether key populations, such as injecting drug users with or without HIV infection, will be included in studies, and another is how cost will affect access to any of the new treatments.
A Nov 4 New York Times story said new HCV medications that are expected to come on the market soon are expected to cost from $60,000 to $100,000 for one course of treatment. The story noted that no international agencies or charities buy HCV drugs, in contrast to drugs for HIV and malaria.
Despite those concerns, Hellard and Doyle write that a single pill that works well for most HCV patients could simplify treatment delivery. “We hope that novel interferon-free combinations—whether sofosbuvir plus ledipasvir or other combinations under development—will fuel interest in how large-scale treatment could lead to the eradication of HCV,” they conclude.
In their trial report, Lawitz and colleagues write that sofosbuvir has already been tested in combination with other experimental antiviral agents. For example, in the COSMOS trial, it was used with the protease inhibitor simeprevir, with and without ribavirin, which yielded SVR rates of 93% to 96%. Another trial paired sofosbuvir with daclatasvir, an NS5A inhibitor, which produced SVR rates of 86% to 100% after 12 weeks.
The recent Times report said Gilead hopes to gain approval for the sofobusvir-ledipasvir combination by the end of 2014. In the meantime, patients with HCV genotype 1 will still need interferon and ribavirin along with sofosbuvir, but for only 12 weeks, the story said.
Other companies, including AbbVie, Merck, and Bristol-Myers Squibb are working to bring all-oral HCV medications to the market in the next 2 years, according to the Times.
Lawitz E, Poordad FF, Pang PS. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet 2013 Nov 5 (early online publication) [Abstract]
Hellard ME, Doyle JS. Interferon-free hepatitis C treatment: one pill to fit all? (Editorial) Lancet 2013 Nov 5 (early online publication) [Excerpt]