Hepatitis C – New classes of medications signify a sea change in therapeutic options.
Since 1998, patients with hepatitis C have had essentially one treatment option: the standard combination of pegylated interferon with ribavirin. While this combination offered a cure rate of about 80% for certain patients, those with genotypes 2 and 3, its cure rate among the most common group, patients with genotype 1, hovered at about 40%. And many patients including those who couldn't tolerate that regimen were essentially out of luck, with no other therapy available.
According to Robert S. Brown Jr., MD, MPH, Director of the Center for Liver Disease and Transplantation, the therapeutic landscape is shifting significantly due to the advent of several new classes of medications that act directly on the virus (Direct-Acting Antivirals or DAA). One class, which includes the FDA-approved protease inhibitors telaprevir and boceprevir, has proven effective enough that the currently recommended standard of care therapy now incorporates one or the other agent in combination with interferon and ribivirin. "The new medications are very potent and effective in clearing the hepatitis C virus," says Dr. Brown. In combination with the older drugs, the addition of either protease inhibitor increases the cure rate to about 80%, in only six months of therapy, in the majority of patients.
This represents a very important advance, according to Dr. Brown. Nevertheless, there is considerable room for improvement. Protease inhibitors have a high rate of resistance, which means that they require the addition of other drugs such as interferon for them to work. They also interact with many other drugs, including the medications required after liver transplantation. Thus, patients who must take these medications, often the sickest, cannot. Furthermore, the medications fail to help many patients who previously failed to respond to standard therapy, and, since they currently require interferon and ribavirin, the new drugs do nothing to help the large number of patients who cannot take these drugs due to their side effects.
Despite these limitations, Dr. Brown is very optimistic about the way that these and other emerging DAA therapies are providing new options, especially to the sickest patients. In addition to the protease inhibitors, other classes of drugs that inhibit the growth or replication of the hepatitis C virus are in development and under active study, both at NewYork-Presbyterian Hospital and elsewhere. These include nucleotides, potent drugs that have little resistance and few drug-to-drug reactions with a low profile of side effects; nonnucleotides, which are less potent and do develop resistance; a class called NS5A inhibitors, which develop resistance but can be a useful component in a multidrug regimen; and others.
"The new direct-acting antiviral drugs are not just less toxic and more potent than older drugs," says Dr. Brown. "The issue is resistance. Interferon and ribavirin weren't working directly against the virus, whereas the newer ones are. Moreover, some of the new drugs are 'pangenotypic': they work on all six types of the virus."
- Over 3 million people in the U.S. have chronic hepatitis C.
- Chronic infection can lead to cirrhosis, liver cancer, and liver failure.
- Hepatitis C is the leading cause of liver transplantation.
- Standard therapy has a cure rate of about 40% in genotype 1, the most common form of hepatitis C.
Proof of Principle: A Cure without Interferon
Telaprevir and boceprevir have not only boosted cure rates when added to interferon and ribavirin, but other DAA combinations have been proven to cure a certain segment of patients without interferon. Although the percentage is relatively low, about 30% in certain patients, newer studies have shown rates approaching 100% with multi-drug, alloral, interferon free regimens. Though the data remains preliminary and the drugs are not yet FDA approved, Dr. Brown explains that the ability to cure patients without interferon represents a very important advance that holds great promise. He believes that it is only a matter of time before effective interferon-free therapy will be available in wider groups of patients. This will be very important, given interferon's substantial side effects: flu-like symptoms, decreased blood counts, worsening of depression, and in patients with advanced liver disease, an association with liver failure.
Trials of interferon-free regimens are currently underway at the Center for Liver Disease and Transplantation. In addition to their potential to yield new therapies for patients with hepatitis C, they may also improve the options available for patients with the virus who undergo liver transplantation for liver cancer. In the past, it has been shown that 12 weeks of interferon-based therapy followed by liver transplantation would cure up to 80% of patients of hepatitis C. The problem was that most patients could not tolerate the pretransplant interferon therapy. At this time, preliminary data suggest that most people can tolerate one of the new drugs, GS7977, and that it can suppress hepatitis C to undetectable levels in most patients. Studies at the Center will see whether the drug is effective in maintaining viral clearance after the transplant.
"These are preliminary studies, but I am very pleased that therapies are being offered to patients who have never before been offered earlier access to new drugs in clinical trials," says Dr. Brown. "In the past, drugs have typically been tested first in the healthiest patients, so it is good to see that patients in the greatest need have access to earlier therapy. So far it appears that the nucleotide class of drugs are well-tolerated, have fewer drug-to-drug interactions, and so if they can cure a substantial number of patients, this will meet an enormous medical need."
Patients are considered cured if they remain free of the hepatitis C virus for six months after therapy is stopped. With triple therapy, the relapse rate is less than 10% within six months. After 6 months, a far smaller number of patients, less than 1%, will undergo a late relapse in the next 5 to 10 years. In patients who do not undergo transplantation, the new drugs clear the hepatitis virus in 80-90% of patients. It is unknown whether that response will be maintained if the liver is removed during transplantation, says Dr. Brown. Studies will need to determine whether patients remain cured of hepatitis long-term after transplant surgery.
In summary, Dr. Brown reiterates his optimism about the prospects for the future. "For many years, the question was 'can we' cure hepatitis in all patients. Now, the big question is not whether, but when will we achieve that goal. The addition of new classes of medications means that we are now working to match the right regimens for each class of patients, which includes consideration of cost, in order to cure everyone. Some patients may be able to be treated with simpler regimens while other, more difficult-to-treat patients, may require different regimens or longer treatment times."