New Orleans—Physicians who treat hepatitis C virus (HCV) infection should prepare themselves for major changes in 2011. One of the most anticipated may be the introduction of direct-acting HCV antiviral drugs, which a series of clinical trials have shown to be highly effective when combined with pegylated interferon (PegIFN) and ribavirin.
Additionally, new methods of patient stratification prior to treatment not only will yield better prognostic information, but also are likely to alter therapeutic approaches regarding the potential benefits and risks of HCV therapy.
“There has been a lot of talk about individualized care, but individualized care will actually become the dominant approach in treatment of HCV,” said Mark S. Sulkowski, MD, medical director of the Viral Hepatitis Center at Johns Hopkins University School of Medicine, in Baltimore.
At the 2010 Digestive Disease Week (DDW) meeting, Dr. Sulkowski summarized many recent developments that he predicts will affect patient management, providing a glimpse of how HCV treatment will change over the next year.
Based on clinical trial data to date, Dr. Sulkowski characterized direct HCV antiviral agents as the first major breakthrough in HCV treatment since the introduction of ribavirin. These direct antivirals may generate sustained virologic response (SVR) rates of approximately 85% among some genotype 1 subgroups, if used optimally.
However, optimal use may not just depend on combination therapy, but also on appropriate pre-treatment patient stratifications. Specifically, identifying the genotype 1 subtype, screening for inosine triphosphate pyrophosphatase (ITPA) deficiency and modifying therapy according to interleukin-28 (IL-28) polymorphisms have the potential to contribute to improved outcomes.
“I think we will be taking into account all three of these new factors and using them, along with the traditional factors, to try to individualize care,” said Dr. Sulkowski, whose list of traditional factors included conventional HCV genotypes and assessment of the stage of liver disease.
Two New Protease Inhibitors Available Soon
By 2011, the first direct HCV antivirals—boceprevir and telaprevir—are expected to be licensed by the FDA. Unlike available agents, these new direct-acting antivirals, which are protease inhibitors, target the HCV particle specifically. The major potential limitation of these agents is a high risk for drug resistance. However, the risk for resistance with either agent is substantially reduced when they are combined with PegIFN and ribavirin, resulting in more effective treatment.
Since Dr. Sulkowski’s lecture at the DDW meeting in May, two Phase III trials of boceprevir have been completed. Both trials evaluated boceprevir in combination with PegIFN and ribavirin. One, called SPRINT-2, was conducted in treatment-naïve patients. The other, RESPOND-2, enrolled patients who had not achieved SVR on PegIFN and ribavirin alone. In both trials, the addition of boceprevir substantially increased SVR rates compared with treatment that did not include boceprevir.
Similarly, three trials in the Phase III program with telaprevir have been completed since the DDW meeting. In HCV treatment–naïve patients, the ADVANCE and ILUMINATE studies have shown that telaprevir in combination with PegIFN and ribavirin led to substantially higher response rates than those observed with the standard treatment. In the REALIZE study, telaprevir was studied in treatment-experienced patients, and investigators found a similar increase in SVR when they added telaprevir to the combination of PegIFN and ribavirin.
Overall, these data show that adding direct-acting HCV antiviral agents to treatment protocols is effective.
Personalized Medicine Becoming a Reality
Dr. Sulkowski also predicts that treatment regimens will become increasingly individualized.
For starters, HCV genotype 1 will be divided into two subtypes—1a and 1b. These subtypes will demarcate different risks for genetic mutations and viral breakthrough. Although there are no hard guidelines on how to individualize treatment based on this differentiation, Dr. Sulkowski believes clinicians will need to be aware of the potential impact of viral subtypes when treating patients with HCV genotype 1 infection.
Additionally, ITPA deficiency has emerged as a clear risk factor for early onset of anemia in patients taking anti-HCV therapy. Although no test for ITPA is currently available, Dr. Sulkowski predicts that it will be soon, and that it may be useful for modifying HCV therapy, such as introducing erythropoietin to increase the likelihood that patients can remain on full doses of their regimen. And although the mechanism explaining why ITPA deficiency increases the risk for anemia in patients on HCV antivirals remains unknown, better methods of predicting this complication may be important because dose reductions or discontinuation of ribavirin has been a major obstacle to achieving SVR in otherwise responsive patients.
The IL-28 polymorphism adds to the complexity of treating HCV. One year ago, a study found that a host genetic polymorphism in a region near the gene for IL28B—a type 3 interferon found on chromosome 19—strongly affects a patient’s response to PegIFN and ribavirin. More recently, there has been considerable speculation as to how this genetic polymorphism will affect a patient’s response to therapy with boceprevir or telaprevir in combination with PegIFN and RBV. In one study, subjects with the favorable IL28B genotype were more than five times as likely to achieve SVR as those with the polymorphism. According to Dr. Sulkowski, there are some preliminary data suggesting that those who have the unfavorable polymorphism should be treated longer for HCV when a direct-acting antiviral is added.
Just the Beginning
Dr. Sulkowski noted that second-generation direct antivirals “are close behind” boceprevir and telaprevir, and that drugs in other classes, including polymerase inhibitors, are also on the horizon.
The new antivirals are attracting much attention in the evolving treatment of HCV infection, but Dr. Sulkowski indicated that better understanding of patient genetic and virus polymorphisms may help to improve treatment outcomes with these new medications.
“The pre-treatment classification of individuals with chronic HCV infection will be increasingly important I think as we move forward,” Dr. Sulkowski said.
Andrew J. Muir, MD, director of gastroenterology/hepatology research at the Duke Clinical Research Institute, at Duke University School of Medicine in Durham, N.C., emphasized the importance of these new developments in HCV.
“After almost a decade with no change in treatment, the addition of the protease inhibitors to our treatment regimen is a tremendous step forward for patients with hepatitis C,” Dr. Muir said. “With the current treatment, most American patients with genotype 1 infection had a 40% chance of cure. We are waiting on final results of the Phase III trials of the protease inhibitors, but it appears that the response rate will increase by approximately 30% with the addition of these medications.”
Like Dr. Sulkowski, Dr. Muir thinks this is just the beginning, noting that “we also have many other antiviral medications in development, and we are very hopeful that treatment will [become] more and more effective.”