The submission of new drug applications to the FDA for two direct-acting antivirals, coupled with an abundance of recent data showing that many more promising agents are in the pipeline, suggests that an interferon-free future for hepatitis C treatment may not be near. For some, it could be available by the end of 2013.
“The most exciting development in hepatitis C are the reports that treatments without interferon have had cure rates of more than 90%,” David Thomas, MD, MPH, professor of medicine and director of the division of infectious diseases at Johns Hopkins University School of Medicine, told Infectious Disease News. “That is the most exciting development in all of medicine right now. No other recent developments in any specialty rival being able to cure more than 90% of people who otherwise would have been at risk for liver failure and liver cancer.”
Interferon-free treatment is considered by most clinicians to be the “holy grail” in HCV treatment. With its undesirable effects on even the healthiest patients, and the fact that many patients are not even eligible for it, interferon is slowly but surely losing its status as the mainstay treatment for HCV.
“A number of studies have found that only approximately 30% of patients with HCV are eligible for interferon therapy,” Marion Peters, MD, professor of medicine and member of the Liver Center at University of California, San Francisco, told Infectious Disease News. “Interferon treatment is difficult for both the patient and the provider, so an interferon-free treatment future is very exciting.”
Infectious Disease News discussed interferon-free treatment with several experts to learn about the most recent data, which drugs are in the pipeline and why such a regimen would be a significant advance for treating HCV.
Tough treatment, modest response
Interferon in some form has been the backbone of treatment for HCV for more than 20 years, since it was approved for this indication by the FDA in 1991. In 1998, the addition of ribavirin to this regimen was approved. In 2001, pegylated interferon was approved, and since then, the standard treatment has been pegylated interferon with ribavirin. In 2011, boceprevir (Victrelis, Merck) and telaprevir
(Incivek, Vertex) were added to the treatment regimen.
Reports of significant HCV cure rates
without interferon are some of the most
exciting developments in all of medicine
right now, according to David Thomas,
Photo courtesy of Weller K/John Hopkins
Although interferon is associated with modest rates of sustained virologic response (SVR), there are many disadvantages to the medication.
“Interferon has significant adverse effects that keep people with HCV from seeking treatment,” Douglas Dieterich, MD, professor of medicine in the divisions of liver disease, gastroenterology and infectious diseases at Mount Sinai School of Medicine, told Infectious Disease News. “Word gets out about the bad experience a patient had with interferon, and then others don’t want to be treated.”
These effects are tough on patients and lead many of them to discontinue treatment. Some patients cannot try the treatment because their condition will not allow them to tolerate it. But those who take interferon must be monitored carefully for the entire duration of treatment.
“For all of these reasons, patients and providers would be very happy to be interferon-free,” Peters said.
There are currently two drugs awaiting review and approval by the FDA. If approved, the first interferon-free regimen will be ready for use.
To date, the most promising interferon-free treatment that has demonstrated success has been sofosbuvir (Gilead) plus ribavirin for the treatment of HCV genotypes 2 and 3. Sofosbuvir is an NS5B nucleotide inhibitor that was submitted to the FDA for approval in April.
Data from two studies of this drug were published in April in The New England Journal of Medicine. In the POSITRON study, 280 patients with HCV genotype 2 or 3 who were unable to receive interferon were randomly assigned to 400 mg sofosbuvir daily plus ribavirin for 12 weeks or placebo. The SVR rate was 78% (95% CI, 72-83) for the sofosbuvir/ribavirin arm vs. 0% for placebo.
In the FUSION trial, 202 patients with HCV genotype 2 or 3 who had previously received treatment were randomly assigned to receive 12 weeks or 16 weeks of sofosbuvir and ribavirin. Among those who received 12 weeks of treatment, the SVR rate was 50%, and among those who received 16 weeks of treatment, the SVR rate was 73%.
In both studies, there were low rates of adverse effects associated with sofosbuvir, and there were no effects on white cell, neutrophil or platelet counts.
“Sofosbuvir with ribavirin has been shown to be very effective for genotypes 2 and 3, but most Americans have genotype 1 and, unfortunately, that regimen is not good enough for those patients,” Andrew Muir, MD, clinical director of hepatology and associate professor of medicine at Duke University, said in an interview. “We expect this interferon-free regimen to be available for genotypes 2 and 3 within the year, but it’s going to take longer for genotype 1. Sofosbuvir and a number of other compounds are being developed in combination for genotype 1 as interferon-free regimens.”
Treatment of genotype 1
Another direct-acting antiviral, an NS3/4A protease inhibitor called simeprevir (Janssen), also has been submitted to the FDA for approval.
In the QUEST-1 study, 394 patients with HCV genotype 1 were randomly assigned to 150 mg simeprevir or placebo, with interferon and ribavirin, for 12 weeks, followed by interferon and ribavirin alone for up to 36 weeks based on response-guided therapy criteria. The SVR rate for the simeprevir group was 80%, and 85% of patients in this group met the response-guided therapy criteria and completed treatment at week 24.
The QUEST-2 study had an identical design. Among those in the simeprevir group, the SVR rate was 81%, and 91% of patients in this group met the response-guided therapy criteria and completed treatment at week 24. The SVR rate in the placebo group for both studies was 50%. Both studies were presented at the 2013 International Liver Congress.
Sofosbuvir also can be used for patients with genotype 1 combined with interferon and ribavirin. In the NEUTRINO study, published in NEJM, 328 patients, most of whom had HCV genotype 1 or 4, received a 12-week regimen that included sofosbuvir, ribavirin and interferon. The SVR rate was 90% (95% CI, 87-93).
Phase 3 data from the STARTVerso1 trial, presented at the International Liver Congress, have shown that faldaprevir (Boehringer Ingelheim), also an NS3/4A protease inhibitor, was associated with improved SVR rates. The 652 patients were randomly assigned to placebo for 24 weeks, 120 mg faldaprevir daily for 12 or 24 weeks according to response-guided therapy, or 240 mg daily for 12 weeks in combination. All patients received 24 weeks of interferon and ribavirin. The SVR rates were 52% for placebo, 79% for 120 mg faldaprevir and 80% for 240 mg faldaprevir.
“Even for the patients who do get interferon, these studies have shown that you can treat with interferon and a direct-acting antiviral for just 12 weeks,” Peters said. “Whichever way you look at it, this is a major advance for all patients, in that the treatment time is much shorter. Most patients can hold on for 12 weeks, but holding on for 48 weeks or more is tough.”
The search for interferon-free regimens for HCV genotype 1 is under way, and there are many other agents in clinical trials. According to Peters, many drugs are being studied in various combinations. All of the drugs target different parts of the HCV genome.
One potential combination is sofosbuvir and simeprevir. Data from the phase 2 COSMOS trial, presented at the 2013 Conference on Retroviruses and Opportunistic Infections, showed that patients who received combination treatment with 150 mg simeprevir and 400 mg sofosbuvir had an SVR rate of 93% without ribavirin and 96% with ribavirin after 12 weeks of treatment.
Sofosbuvir also is being studied combined with ledipasvir (Gilead), an NS5A nucleotide inhibitor. In the ELECTRON study, the results of which were also presented at CROI, the combination of sofosbuvir, ledipasvir and ribavirin led to a 100% SVR rate at 12 weeks among 25 treatment-naive patients and nine null responders. The sofosbuvir and ledipasvir combination is now being tested with and without ribavirin, for 12 and 24 weeks, in ION-1, a phase 3 trial.
A drug regimen developed by AbbVie, including ABT-450 with ritonavir, ABT-267, ABT-333 and ribavirin, showed promise in the results of the phase 2b Aviator study, presented at the International Liver Congress. For treatment-naive patients, the SVR4 rates were 98.7% for those who received 12 weeks of treatment and 96.2% for those who received 24 weeks of treatment. For null responders, the SVR4 rates were 93.3% and 97.7%, respectively.
More drugs are in development, including Bristol-Myers Squibb’s daclatasvir and asunaprevir, Vertex’s VX-135 and Merck’s MK-5172, vaniprevir and MK-8742. Many companies are working together to test combinations of their respective drugs.
Resistance and cost
There are very few drawbacks to these new medications, which make treatment more convenient, have fewer adverse effects and can be used by the sickest patients.
“From the perspective of the patient and the provider, it is a fabulous breakthrough to have a medication that is not only more convenient, but also safer,” Thomas said. “At the same time, we are also increasing the efficacy of treatment considerably, which in itself is a reason for the mounting enthusiasm surrounding these drugs.”
There is concern about resistance. According to Peters, the drugs are always used in combination, either with another direct-acting antiviral or interferon and ribavirin, because of the potential for resistance if the drugs are used alone. Protease inhibitors have shown the most resistance, but the nucleotide inhibitors appear to have the least resistance. According to Dieterich, resistance to sofosbuvir has only been seen in one patient.
In a study presented at the International Liver Congress, patients who failed treatment with and were resistant to telaprevir or boceprevir were treated with sofosbuvir and daclatasvir, an NS5A inhibitor. The SVR4 rate was 100% after 24 weeks of treatment, both with and without ribavirin.
“This should reassure both patients and professionals that protease resistance can be overcome by using combinations of drugs from other classes,” Dieterich said.
Peters also said the studies so far have been in mostly otherwise healthy patients. Many patients with HCV also have other health problems that could potentially cause adverse events that may not have been seen in the healthy patients.
Also, another area of concern is the cost.
“We assume that these drugs will not be cheap,” Muir said. “The cost is a potential barrier, but we don’t know yet.”
Until the drugs are approved by the FDA, there is no idea what these drugs will cost or whether health insurance companies will pay for them, especially if they are used off label.
“If sofosbuvir and simeprevir are approved and available by the end of this year, which we think they will be, the data support that this would be the most reasonable combination for patients with HCV genotype 1,” Dieterich said. “However, I’m sure that insurance companies won’t pay for it. This is not going to be like the old days of HIV, where you can use any combination of drugs that was reasonable.”
Public health benefit
Peters and Muir said these new regimens are a game changer.
The idea that treatment for HCV will be much more convenient and tolerable may have an effect on the general public: It may encourage people at higher risk for HCV to be tested and then treated for the disease.
“The complicated treatment is a significant barrier to widespread screening and treatment,” Muir said. “Many patients can’t or won’t undergo treatment. It’s incredibly exciting and rewarding to be able to offer all patients with hepatitis C a chance to be cured.”
Thomas echoed this thought.
“Safer and more effective treatment for HIV led to expanded treatment, siphoning more people into the system and having a great public health impact,” Thomas said. “We are hoping that the same will happen for hepatitis C.”
Thomas said he predicts that by the end of 2014, there will be a number of FDA-approved, interferon-free regimens available for all patients with hepatitis.
“Interferon has been the ‘workhorse’ for hepatitis C treatment for quite some time,” Thomas said. “There will still be a need for interferon in some cases, but it will no longer be the preferred treatment. That’s exciting news.” – by Emily Shafer
Ferenci P. #1416. Presented at: 2013 International Liver Congress; April 24-28, 2013; Amsterdam.
Gane E. #41LB. Presented at: 2013 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta.
Kowdley K. #3. Presented at: 2013 International Liver Congress; April 24-28, 2013; Amsterdam.
Jacobson I. N Engl J Med. 2013;doi:10.1056/NEJMoa1214854.
Jacobson I. #1425. Presented at: 2013 International Liver Congress; April 24-28, 2013; Amsterdam.
Lawitz E. #155LB. Presented at: 2013 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta.
Lawitz E. N Engl J Med. 2013;doi:10.1056/NEJMoa1214853.
Manns M. #1413. Presented at: 2013 International Liver Congress; April 24-28, 2013; Amsterdam.
Sulkowski M. #1417. Presented at: 2013 International Liver Congress; April 24-28, 2013; Amsterdam.
For more information:
Douglas Dieterich, MD, can be reached at: Icahn School of Medicine at Mount Sinai, Annenberg 21-42, New York, NY, 10029; email: firstname.lastname@example.org.
Andrew Muir, MD MHS, can be reached at Duke Clinical Research Institute, PO Box 17969, Box 3850, Durham, NC 27715; email: email@example.com.
Marion Peters, MD, can be reached at: UCSF, GI Division, Room S-357, 513 Parnassus Ave., San Francisco, CA, 94143-0538.
Disclosure: Thomas has financial relationships with Gilead, Janssen and Merck. Muir has financial relationships with Abbott, Bristol-Myers Squibb, Gilead, Merck, Novartis and Vertex. Peters has financial relationships with Clinical Care Options, Genentech, Merck, Roche and Theravance. Dieterich has financial relationships with Achillion, Boehringer Ingelheim, Gilead, Idenix Pharmaceuticals, Janssen, Merck and Vertex.
How will genotype 1 hepatitis C be treated until there is an all-oral combination available for this group of patients?
It’s a matter of weighing the risk and benefits.
What’s interesting about hepatitis C is that people have had the disease for decades and there is rarely an urgent issue to treat right away. There are exceptions, such as people who have aggressive hepatitis C recurrence after liver transplants or who have cirrhosis. In these patients, who have an immediate need for treatment, I will treat with the interferon-based therapy. Most patients, however, can wait 6 months, a year, or even years before undergoing treatment. Within the next 2 years, we will likely have new drug combinations approved for genotype 1 that will consist of an all-oral regimen. These all oral combination therapies will have high cure rates, and will likely be associated with few adverse effects. Fortunately, the majority of patients with hepatitis C can wait until these agents are approved to begin treatment. This is a very exciting time for hepatitis C.
Sammy Saab, MD, MPH, AGAF, is a professor of medicine and surgery, David Geffen School of Medicine, University of California, Los Angeles. Disclosure: Saab has financial relationships with Bristol-Myers Squibb, Genentech, Gilead, Kadman, Merck, and Vertex.
The floodgates for hepatitis C treatment will not open until all oral therapy is available.
Some oral combinations have shown a success rate of 100% in early trials, and we expect these drugs to be fast-tracked through the FDA. There is going to be a continued reluctance to have patients with hepatitis C start therapy until all-oral therapy is available. In patients with IL28B genotype CC, the success rate with interferon, ribavirin and sofosbuvir is 98%. When the success rate is that high, it may not be ethical to wait until more convenient therapy is available. But it will depend on the individual patient. There are some people who shouldn’t wait the extra 2 to 3 years to start therapy, particularly those who have symptoms or hepatic fibrosis and those who are at risk for advanced liver disease. There will definitely be a place for interferon-based triple therapy in those patients and in patients who don’t want to wait for treatment. This is a disease that plays out over 30 years, not 30 months. For many people, waiting 30 months for a safer, more effective treatment will not be a big deal.
William Carey, MD, MACG, is a hepatologist, Cleveland Clinic. Disclosure: Carey reports no financial disclosures.