Studies presented at the EASL International Liver Congress, held April 24–28 in Amsterdam, confirm the expectation that a new generation of safer and more effective therapies for hepatitis C will be available within the next few years. These include both better add-ons to interferon and the first interferon-free combinations of direct-acting antivirals (DAAs).
An estimated three million people in the U.S. have hepatitis C, but most do not know they’re infected. The CDC this week reiterated its recommendation that all “baby boomers” born between 1945 and 1965 get a test for HCV antibodies and, if positive, a viral load test to determine if they’re still infected. “You may not remember what you did in the 60s and 70s, but your liver does,” said CDC director Thomas Frieden.
Testing is crucial because chronic HCV infection can lead to cirrhosis, liver cancer, and death. Now is a good time because better hepatitis C treatments that can stop liver disease progression are on the way.
The current standard of care adds one of the first approved DAAs—boceprevir (Victrelis) or telaprevir (Incivek)—to pegylated interferon and ribavirin. Triple therapy works better than interferon/ribavirin alone, but comes with added side effects.
Some people with advanced liver disease cannot wait for better options, but data presented at the EASL meeting show that these regimens carry a high risk of serious complications for patients with cirrhosis and liver transplant recipients.
For people who can wait a bit longer, several studies showed promising outcomes when adding more effective and better-tolerated second-generation DAAs to interferon-based therapy:
- Daclatasvir (HCV NS5A inhibitor)
- Faldaprevir (HCV protease inhibitor)
- MK-5172 (HCV protease inhibitor)
- Simeprevir (HCV protease inhibitor)
- Sofosbuvir (nucleotide analog HCV polymerase inhibitor)
- Vaniprevir (HCV protease inhibitor)
These new drugs produced cure rates in the 80% to 90% range even for difficult-to-treat patients. They can often shorten treatment to three to six months (down from six months to a year) and generally do not cause more side effects than interferon and ribavirin alone. (For more detailed coverage of this study and others presented at EASL 2013, visit HIVandHepatitis.com.)
“DAAs are ready for prime time,” EASL Secretary General Mark Thursz said at an April 24 press conference kicking off the congress.
The first new DAAs are expected to become available by late 2013 or early 2014, initially for use with interferon. Simeprevir and sofosbuvir were submitted for FDA approval in March and April, with a review timeline of six months.
“Interferon is not dead yet,” Thursz emphasized. “Twelve weeks of an interferon triple regimen is tolerable for a large number of patients…and it may be better than waiting another year for a suitable all-oral regimen.”
People with early or stable liver disease may be able to wait for all-oral regimens that eliminate interferon, which can cause flu-like symptoms and depression. Some combos also dispense with ribavirin, which can cause anemia.
All-oral regimens have gotten the lion’s share of attention at recent conferences (including the Conference on Retroviruses and Opportunistic Infections in March). While several interferon-free regimens continue to look good, enthusiasm at EASL was somewhat tempered by setbacks among difficult-to-treat patients.
A quad regimen containing DAAs developed by AbbVie (formerly Abbott)—HCV protease inhibitor ABT450 boosted with ritonavir + NS5A inhibitor ABT-267 + non-nucleoside polymerase inhibitor ABT-333 + ribavirin—cured 96% of treatment-naive patients with HCV genotype 1 and 93% of prior interferon non-responders treated for 12 weeks in the Aviator study.
This combo is especially promising because it worked for more than 90% of previously untreated or treatment-experienced patients, people with harder-to-treat HCV subtype 1a or easier-to-treat 1b, and those with mild or moderate liver fibrosis, though people with cirrhosis—who have the poorest response—were excluded.
AbbVie announced this week that the FDA has given this regimen a “breakthrough therapy” designation, intended to speed development and review of promising drugs for serious or life-threatening conditions.
Gilead’s sofosbuvir/ribavirin 12-week dual regimen previously demonstrated 100% sustained virological response (SVR) for previously untreated people with HCV genotypes 2 or 3 and no liver cirrhosis. SVR at 12 or 24 weeks after completing treatment (known as SVR12 and SVR24) is considered a cure.
But researchers at EASL reported lower cure rates in the larger treatment-naive FISSION and treatment-experienced FUSION trials, in which 20%–30% of participants had cirrhosis. SVR12 rates were 67% using a 12-week regimen in FISSION, and 50% with a 12-week regimen or 73% with a 16-week regimen in FUSION.
The major surprise was that people with genotype 2 and genotype 3—usually considered together as a single “easier-to-treat” category compared with genotype 1—responded differently.
Among those with genotype 2, SVR rates were excellent: 97% in FISSION and 86%–94% in FUSION. People with genotype 3 did not fare as well, with cure rates of 56% and 30%–62%—no better than pegylated interferon/ribavirin. The difference was even more pronounced among people with cirrhosis, with cure rates falling as low as 34% in FISSION and 19% in FUSION.
Presenter Edward Gane from Auckland City Hospital suggested that genotypes 2 and 3 should no longer be lumped together, as genotype 3 is “behaving as a harder-to-treat virus.”
Turning to genotype 1, further results from the ELECTRON trial confirmed that sofosbuvir/ribavirin alone is not adequate for such patients. Adding the NS5A inhibitor ledipasvir, however, raised the cure rate to 100% for both treatment-naives and prior null responders.
Gilead announced last week that a coformulation of sofosbuvir/ledipasvir without ribavirin for eight or 12 weeks led to 95%–100% sustained response at four or eight weeks post-treatment—promising, but too soon to declare a cure.
Study findings reported in 2012 showed that sofosbuvir plus Bristol-Myers Squibb’s NS5A inhibitor daclatasvir cured 100% of treatment-naive genotype 1 patients. Gilead decided not to pursue this combination in Phase 3 trials in favor of its own ledipasvir, but some smaller studies have gone forward.
Mark Sulkowski from Johns Hopkins University reported that sofosbuvir plus daclatasvir cured all previously treated genotype 1 patients who did not respond to interferon-based triple therapy using boceprevir or telaprevir, providing some of the first data on “rescue therapy” after failure of the current standard-of-care.
Finally, a three-drug DAA combo containing daclatasvir, the HCV protease inhibitor asunaprevir, and the non-nucleoside polymerase inhibitor BMS-791325, taken for 12 or 24 weeks, cured 88%–94% of previously untreated genotype 1 patients without cirrhosis, with treatment “failures” mostly due to missing data rather than viral breakthrough or relapse.
Taken together, these findings add to the evidence that effective and well-tolerated DAA therapy will be able to cure most people with chronic hepatitis C within the coming years.
“If a patient has early stage [liver disease], lots of physicians are recommending their patients wait” for all-oral regimens, Thursz summarized. For those with more advanced disease, “treating with the standard of care is probably the way to go”—unless they have very advanced disease, in which case they have “significant risk of dying from septic complications” if treated with current triple therapy.
Liz Highleyman (liz (at) hivandhepatitis.com) is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.
AbbVie. AbbVie’s Investigational HCV Regimen Receives Breakthrough Therapy Designation from the U.S. Food and Drug Administration. Press release. May 6, 2013.
Bristol-Myers Squibb. High Rates of SVR Demonstrated in Phase II Study with Investigational Triple DAA Regimen of Daclatasvir, Asunaprevir and BMS-791325 in Treatment-Naive Patients with Genotype 1 Chronic Hepatitis C Infection. Press release. April 23, 2013.
Everson, G. and others. Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24–28, 2013. Abstract 1423.
Ferenci, P. and others. Faldaprevir plus pegylated interferon alfa-2A and ribavirin in chronic HCV genotype-1 treatment-naive patients: final results from STARTVerso1, a randomised double blind placebo-controlled phase III trial. Abstract 1416.
Fontaine, H. and others. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non responders treated in the French Early Access Program (ANRS CO20-CUPIC). EASL 2013. Abstract 60.
Gane, E. and others. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naive GT2/3 HCV-infected patients (FISSION). EASL 2013. Abstract 5.
Gane, E. and others. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. EASL 2013. Abstract 14.
Gilead Sciences. Gilead reports interim data from Phase 2 LONESTAR study. Press release. May 2, 2013.
Jacobson, I. and others. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. New England Journal of Medicine. April 23, 2013 (Epub ahead of print).
Jacobson, I. and others. Treatment with sofosbuvir+ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. EASL 2013. Abstract 61.
Jacobson, I. and others. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve patients: results from QUEST-1 a phase III trial. EASL 2013. Abstract 1425.
Kowdley, K. and others. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267 and ABT-33 +/- ribavirin in patients with chronic genotype 1 infection: results from the Aviator study. EASL 2013. Abstract 3.
Lawitz, E. and others. Sofosbuvir for previously untreated chronic hepatitis C infection. New England Journal of Medicine. April 23, 2013 (Epub ahead of print).
Lawitz, E. and others. Sofosbuvir + peginterferon + ribavirin for 12 weeks achieves 90% SVR12 in genotype 1, 4, 5, or 6 HCV infected patients: the NEUTRINO study. EASL 2013. Abstract 1411.
Manns, M. and others. High sustained viral response at 12- and 24-week follow-up of MK-5172 with pegylated interferon alfa-2b and ribavirin (PR) in HCV genotype 1 treatment-naive non-cirrhotic patient. EASL 2013. Abstract 66.
Manns, M. and others. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: results from QUEST-2 a phase III trial. EASL 2013. Abstract 1413.
Nelson, D. and others. All oral therapy with sofosbuvir+ribavirin for 12 or 16 weeks in treatment experienced GT2/3 HCV-infected patients: results of the phase 3 FUSION trial. EASL 2013. Abstract 6.
Rutter, K. and others. Safety of triple therapy with telaprevir or boceprevir in hepatitis C patients with advanced liver disease – predictive factors for sepsis. EASL 2013. Abstract 65.
Sulkowski, M. and others. Sustained virologic response with daclatasvir plus sofosbuvir +/-± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). EASL 2013. Abstract 1417.
Verna, E. and others. A multicenter study of protease inhibitor-triple therapy in HCV-infected liver transplant recipients: report from the CRUSH-C group EASL 2013. Abstract 23.