This week’s NEJM features two studies (ION-1 and ION-3) that examine ledipasvir, a NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, for previously untreated HCV infection. A recent search of the New England Journal of Medicine archives for the term “HCV” returned 45 original research articles from the last 5 years. For many of us, the significance of a highly effective regimen that is interferon/ribavirin-free may get lost among the other 45 papers if one does not grasp the long road taken to get to this point.
Since the 1990s, the mainstay of hepatitis C treatment has been interferon plus ribavirin. For those with HCV genotype 1, interferon/ribavirin produced sustained virologic response (SVR) rates of 40%. Coupled with its significant side effects (flu-like symptoms, cytopenia/anemia and rash), this regimen left most providers hoping for more effective and less caustic options.
Beginning in 2009, research published in the Journal found the addition of a novel HCV protease inhibitor (boceprevir or telaprevir) to interferon/ribavirin regimens could induce SVR rates in treatment-naïve (SPRINT-2 and PROVE1) and treatment-resistant (RESPOND-2) individuals as high as 68%. Two years later, the Journal published the FISION/NEUTRINO trial demonstrating SVR rates as high as 90% with the addition of sofosbuvir to interferon/ribavirin for persons with previously untreated HCV.
Subsequently, the FDA individually approved telaprevir, boceprevir and subfosbuvir for use in concert with interferon and ribavirin. Despite the significant improvement in clinical outcomes, these landmark studies still reported a high frequency of adverse events traditionally associated with interferon/ribavirin. No FDA-approved treatments were available to liberate patients with HCV Genotype 1 from interferon/ribavirin regimens and their significant side-effects.
In April 2014, the Journal published SAPPHIRE-I and SAPPHIRE-II, which looked a multidrug interferon-free regimen of ABT-450/r (protease inhibitor), ombitasvir (NS5A inhibitor), dasabuvir (nonnucleoside NS5B) and ribavirin for untreated and previously treated genotype 1 infection. SVR rates were as high as 96% and statistically superior to historical SVRs achieved with the interferon/ribavirin plus telaprevir or boceprevir regimens described above. Although discontinuation due to adverse events was rare (0.6% of subjects) and never a result of anemia, ribavirin-related side effects such as fatigue, headache, nausea and pruritis were common, as were reductions in hemoglobin level.
In the last month, the Journal published three studies, ION-1, ION-2, and ION-3, which detail a new regimen for treatment of genotype 1 that does not depend on either interferon or ribavirin. As reported here last month, ION-2 showed superiority of sofosbuvir and ledipasvir over historical SVRs for previously treated HCV genotype 1 infection, and non-inferiority to a regimen of sofosbuvir, ledipasvir and ribavirin of similar duration.
In this week’s Journal, ION-1 and ION-3 demonstrate similar results in previously untreated patients. ION-1 compares SVRs for sofosbuvir and ledipasvir to sofosbuvir, ledipasvir plus ribavirin in both 12-week and 24-week regimens. ION-3 examines the effectiveness of a shorter duration treatment option by comparing 8 weeks of sofosbuvir and ledipasvir, 8 weeks of sofosbuvir and ledipasvir plus ribavirin, and 12 weeks of sofosbuvir and ledipasvir. In each study, the rates of response were superior to historical controls (between 93% and 99%) and did not significantly vary across groups that traditionally demonstrated poor response to interferon-based regimens. The groups receiving only sofosbuvir and ledipasvir had a lower incidence of anemia, hyperbilirubinemia and overall frequency of adverse events than the groups receiving ribavirin.
So what do the ION trials and SAPPHIRE-I mean for the medical and patient community? These studies may mark a significant change in our expectations for therapy. Physicians may find themselves asking “how effective is effective enough?” Patients may need to consider “how much side effect burden is too much?” Does ribavirin offer any value in effectiveness to offset side effects? The answers to these questions will need to be considered in the context of cost as well. As discussed by Drs. Hoofnagle and Sherker in their accompanying editorial, “the predicted costs of the new oral antiviral agents are as breathtaking as their effectiveness”.
Although FDA approval for the drugs examined in SAPPHIRE and ION are pending, there is already much excitement about the move to interferon-free and interferon/ribavirin-free treatment options for Hepatitis C. As NEJM Deputy Editor Dr. Mary Beth Hamel notes, “The recent development of treatment regimens for hepatitis C that are not only highly effective, but also easy to administer and well tolerated, offers the opportunity to substantially reduce the global burden of hepatitis C and save many lives.”