As new drugs become available for the treatment and cure of hepatitis C (HCV), researchers look to develop regimens that are shorter, more tolerable and have better success rates. We asked Dr. Hugo Vargas, Professor of Medicine, Mayo Clinic College of Medicine, and Regional Medical Advisor to the American Liver Foundation, to discuss current and future hepatitis treatments, along with recent research.
What are the latest changes in hepatitis C treatment?
Let me rewind to the end of 2013. At that time there were two regimens considered to be the standard of care for patients with genotype 1, which constitutes about 70 percent of the HCV infected population in America. They included two drugs in the Protease Inhibitor (PI) class. One was called boceprevir and the other was called telaprevir. They were very important improvements from what we had before, but they still required interferon and another drug called ribavirin. The use of these two drugs resulted in a 70 percent change in curing infection in patients infected with genotype 1 HCV.
But then, at the end of 2013, the Food and Drug Administration (FDA) cleared both sofosbuvir, which the trade name is Sovaldi, and then simeprevir, which is Olysio. They were both approved in the same time frame, but the regimens for treatment differ and they belong to different drug classes.
How do you treat hepatitis C with Sovaldi?
The drug that is causing most excitement is Sovaldi. Sovaldi is a nucleotide Polymerase Inhibitor. Its approval was for genotypes 1, 2,3,4,5, and 6. How the drug is combined and for how long it is used varies. The most common viral type, genotype 1, should be treated with pegylated interferon, which is given once a week, ribavirin, which you take twice a day, and Sovaldi, which is taken once a day. Response rates are in the high 80 to 90 percent in this viral genotype. For patients who have viral genotype 2, it’s even simpler; patients take Sovaldi and ribavirin for 12 weeks. And patients who have genotype 3 have the option of taking Sovaldi and ribavirin for 24 weeks, or they can take Sovaldi, ribavirin and pegylated interferon for 12 weeks. Those regimens have similar effectiveness. For genotypes 4, 5 and 6, patients are treated as the patients who have genotype 1 virus.
So you see that already there is a mix of treatments for genotypes 2 and 3 and the FDA has approved interferon-free regimens. A lot of people have been waiting for this moment.
How do you treat hepatitis with Olysio?
The other medication that was approved was Olysio. Olysio is a next generation PI. It is approved for genotype 1, and the regimen lasts for 24 to 48 weeks, with a combination of Olysio taken once a day, pegylated interferon and ribavirin for 12 weeks, and then patients complete either 12 weeks or 36 weeks of interferon, depending on how the patient has responded to the treatment while on therapy.
What are the advances in treatment for patients who are interferon-intolerant?
The thing that has a lot of people excited about is that the company that owns the rights to Olysio did some studies early on, before Gilead purchased sofosbuvir, combining simeprevir and sofosbuvir, and studied difficult-to-treat patients. So that regimen includes simeprevir and sofosbuvir, without ribavirin, for 12 weeks, and gives you a very solid response rate. But, unfortunately, this regimen is not FDA-approved.
For now, that’s the only interferon-free regimen for patients with HCV genotype 1 infection who are intolerant of interferon, (they have some contraindication to IFN or will not accept IFN). The FDA has allowed for genotype 1 to receive sofosbuvir for a total of 24 weeks combined with ribavirin, for patients who are not interferon tolerant. But, that’s 24 weeks with ribavirin and the response rates are in the 70 percent range for the hardest to treat individuals, while sofosbuvir and simeprevir, which is also interferon-free, is taken for 12 weeks with response rates in the high 80s low 90s.
What was the most exciting research from the International Liver Conference in London?
In the London meetings, it became apparent that the combination of sofobuvir with another agent called ledipasvir, (a direct antiviral in the N5A complex inhibitor class) in a single pill, is very effective in treating patients with genotype 1 for as short as eight weeks without ribavirin in the right circumstances. Potentially this combination may be used for patients infected with genotype 3 (combined with ribavirin, which early studies suggest can clear the disease in 24 weeks). Both are interferon-free regimens with high response rates.
This combination may be used in patients who have never been treated, who have not responded in the past, and there has even been data on patients with cirrhosis. The regimen is well tolerated and large percentages cleared the virus. It is my hope that this medication, currently being reviewed for approval by FDA, will be made available this year to treat patients outside of trials.
Another avenue for treatment was represented by the regimen being developed by another company, AbbVie. The regimen is comprised of three direct antiviral agents, as well as ribavirin. Patients take a PI (ABT 450) a non-nucleotide Polymerase inhibitor (dasabuvir) and an agent in the NS5A inhibitor class
(ombitasvir) for 12 to 24 weeks with excellent long-term response. The regimen has been studied in Genotype 1. Most patients will be able to clear virus in 12 weeks. The regimen combines ABT 450, ombitasvir, and ritonavir (as a booster to allow once/day dosing of ABT 450) in a single pill, in addition to dasabuvir and ribavirin twice per day. These studies also looked at patients who were naïve to therapy, experienced to therapy but failed, and those who had cirrhosis or a liver transplantation. All subgroups had very high rates of response - above 90 percent.
Bristol Meyers and Merck also have very exciting new agent combinations that are going to simplify the treatment of HCV in the near future.
What about specific populations with hepatitis C?
Populations that are felt to have a high need include patients with cirrhosis, those who have transplanted livers and have recurrent HCV, patients on hemodialysis and those who are HIV co-infected. Almost all of those populations should benefit from the new drugs. We still need to consider how children will respond to treatment, and how those who are incarcerated or actively using injected drugs will be reached.
What will the cost be, and how will people get coverage?
The difficult part of this new era is that new medications will cost a lot of money. At Digestive Disease week in Chicago, researchers presented some early modeling using the data from clinical trials. They suggest that for some populations, clearing the virus, despite the high cost of medication, may lead to benefits in life quality and reductions in future expenditure that may make the medication cost effective.
All of this is in the background of the Centers for Disease Control and Prevention now strongly recommending that primary care doctors test the hepatitis C status of baby boomers. A lot of patients are likely to find out that they have hepatitis C and now the question is, how will we pay for them and how will this be covered? This very timely question will lead to analysis of how these new excellent regimens can affect the outcome of these patients.
What does the future of hepatitis C treatment look like?
The reality is that there are a least four pharmaceutical companies that have very mature pipelines, with products that are very exciting. I don’t think they have any intention in slowing down in developing regimens that are simpler, better tolerated, and hopefully are of shorter duration. I think already we see the day that many patients who we would have treated for six months to a year now may be treated from eight weeks to maybe as long as six months.
We’re really decreasing the duration of care, making it easier because they don't have to inject their medications, and the side effects of these cures have decreased significantly. This will hopefully translate into regimens that are easier for doctors to recommend and implement. I think the future is very bright and very exciting. We cannot forget that advocacy for patients and their need is more urgent than ever, particularly given the cost of a cure.
Any hope for a hepatitis C vaccine?
It has proven very challenging to create a hepatitis c vaccine. The question that one has to ask is, if we have a drug regimen that gives you 90 percent-plus response rate, do we need a vaccine? While this may remain a very solid goal to pursue, it is my suspicion that the urgency to develop a vaccine has decreased in the face of recent successes.