By Annette M. Boyle
WASHINGTON — New therapies for hepatitis C (HCV) are pouring out of the pharmaceutical pipeline and promising effective treatment with fewer side effects for many of the 170,000 veterans with chronic HCV in care at VA facilities. Several options have demonstrated very effective viral suppression without relying on either ribavirin or interferon, the highly problematic mainstays of current treatment.
The largest provider of HCV care in the country, the VA cares for 5% of all known HCV patients in the United States. “The VA is credited as the national leader in screening, confirmation testing and treatment for HCV,” said David Ross, MD, PhD, director of the HIV, HCV, and public pathogens programs at the VA. As a result, providers have a keen understanding of the challenges posed by the current therapies, which include pegylated interferon, ribavirin and one of two Food and Drug Administration-approved protease inhibitors, boceprevir or telaprevir.
“The problem up to now has been that interferon has low cure rates and is horribly toxic, which really affects adherence, and adherence is a key predictor of success,” he noted. “Ribavirin is no walk in the park either. Patients suffer severe anemia and rash; some have to have blood transfusions or take growth factor to combat anemia.”
The standard dual therapy for HCV genotype 1, which accounts for about 80% of HCV infections, requires patients to take interferon and ribavirin for 48 weeks. “People feel like they have a bad flu for a year. They are terribly depressed, and the treatment increases the rate of suicide among patients,” Ross told U.S. Medicine.
The addition of the protease inhibitors to the treatment regimen in 2011 increased adherence and sustained virologic response and reduced the length of treatment, but the “newer treatments are extremely complicated. The response-guided therapy determines whether treatment should stop after eight or 12 weeks, and patients must take pills every eight hours — not three times a day,” he added.
New treatments approved by the FDA, awaiting approval or completing phase 2 trials report high rates of viral suppression with far fewer side effects and much simpler regimens.
“We’re seeing interferon-free regimens coming down the line and also some without ribavirin,” Ross said. “We’re really excited about the potential for these drugs. In fact, we held a meeting specifically for VA providers at the American Association for the Study of Liver Diseases (AASLD) meeting to discuss when these new drugs would be available and how to get them.”
Interferon, Ribavirin-free Therapies
In October, the FDA’s Antiviral Drugs Advisory Committee unanimously recommended approval of sofosbuvir, a nucleotide analog N25B polymerase inhibitor, with ribavirin alone for treatment of HCV genotypes 2 and 3. “For genotypes 2 and 3, sofosbuvir without interferon had phenomenal cure rates,” Ross said.
The committee also recommended sofosbuvir with interferon and ribavirin in the more difficult to treat genotype 1 as well as for genotype 4. The addition of sofosbuvir reduced the length of treatment to 12 weeks.
Ribavirin and interferon might not be needed much longer, however. Results of a Phase 2 trial presented at AASLD and published in The Lancet showed that sofosbuvir in a single-pill combination with ledipasvir, a NS5A inhibitor, produced 95% to 100% sustained virologic response 12 weeks after treatment (SVR12) in patients. One hundred patients participated in the study. The results were consistent with or without the addition of ribavirin, regardless of previous treatment history or the presence of compensated cirrhosis.1
Results of a Phase 3 trial in Japan presented at the same meeting demonstrated an 85.6% SVR12 to an oral therapy that combined daclatasvir and andasunaprevir, without either ribavirin or interferon. The 24-week study enrolled 222 patients with genotype 1 HCV who were ineligible, intolerant or naïve to the standard therapy or previously had not responded to it. Daclatasvir is an HCV NS5A replication complex inhibitor, and asunaprevir is an NS3 protease inhibitor.2
Other researchers reported at ID Week 2013 that a triple-drug regimen that included daclatasvir, asunaprevir and BMS-791325, a non-nucleoside NS5B polymerase inhibitor, vanquished the virus in 89% to 94% of patients at 12 weeks after the conclusion of therapy. To date, 66 treatment-naïve patients with genotype 1 HCV have participated in the study. The study compared results after 12 and 24 weeks of treatment and using 75 mg and 150 mg of BMS-791325 and found little difference among the four arms.3
Last month, the FDA approved Olysio (simeprevir), a protease inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. It is to be used as a component of a combination antiviral treatment regimen. In clinical studies, Olysio was evaluated in combination with peginterferon-alfa and ribavirin, two drugs also used to treat hepatitis C virus infection.
Olysio is intended for treatment naïve adults with compensated liver disease, including cirrhosis, or patients for whom previous treatment has not been effective.
Approval was based on Phase 3 trial results that showed an approximately 80% SVR12 rate in both treatment naïve and relapsers with the addition of simeprevir compared to 50% with the dual therapy alone.
Another protease inhibitor, danoprevir, achieved strong results in a Phase 2 trial with previously untreated patients with HCV genotype 1, according to a study recently published in Gastroenterology. When added to ribavirin and interferon, danoprevir reduced detectable virus levels by nearly half within one week. Researchers reported that 85% of patients receiving 600 mg of danoprevir had no detectable virus six months following treatment and 79% were eligible for shortened treatment duration.4
“Many of the direct acting agents (DAAs) under investigation offer benefits to existing DAAs (boceprevir and telaprevir) in terms of duration of treatment—12 or 24 weeks compared to 24 or 48 weeks with existing DAAs,” said Pamela Belperio, PharmD, national public health clinical pharmacist for the VA Office of Public Health.
The newer agents also offer “simplified regimens in that they do not require response guided therapy and futility monitoring and have SVR rates that are higher for most patient populations,” she told U.S. Medicine.
While in clinical trials the newer agents are showing SVR rates of 80% to 90%, in routine practice the rates will likely be lower, Belperio predicted. In real world practice, SVR rates with the current protease inhibitors are 50% (boceprevir) and 52% (telaprevir) or 10% to 15% lower than achieved in clinical trials, according to a recent VA study published in Alimentary Pharmacology and Therapeutics.5
1 Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, Symonds WT, McHutchison JG, Membreno FE. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naïve and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trial. The Lancet, Early Online Publications, 5 November 2013.
2 All-oral combination of daclatasvir plus asunaprevir in interferon ineligible naïve/intolerant and nonresponder Japanese patients chronically infected with HCV genotype 1b: Results from a phase 3 trial. AASLD 2013
3 Rodriguez-Torres M, et al. 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. ID Week 2013; Abstract 1828.
4 Marcellini P, Cooper C, Balart L, Larrey D, Box T, et al. Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection. Gastroenterology. 2013 June;145(4):790-800.
5 Backus, L. I., Belperio, P. S., Shahoumian, T. A., Cheung, R. and Mole, L. A. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort. Alimentary Pharmacology & Therapeutics. First published online 10 Nov 2013.