New Hepatitis C Drugs Highly Effective but Access Could Be a Challenge
November 19, 2013
Effective new treatments for hepatitis C, including for difficult-to-treat groups such as people with liver cirrhosis and HIV/HCV coinfection, were the focus of the Liver Meeting, the 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD), held this month in Washington, DC.
Direct-acting antiviral drugs (DAAs) that target different steps of the hepatitis C virus lifecycle have brought about a revolution in treatment. The old standard of care, pegylated interferon plus ribavirin, cured fewer than half of people with hard-to-treat genotype 1 HCV with a year of treatment that causes side effects ranging from flu-like symptoms to depression.
Adding one of the first DAAs approved in 2011, boceprevir (Victrelis) or telaprevir (Incivek), increases cure rates to about 60%-70% and can shorten treatment to six months, but they come with their own toxicities. In contrast, several of the next-generation DAAs described at the Liver Meeting offer cure rates upwards of 80%-90% with minimal side effects.
On the final day of the conference, Mark Sulkowski from Johns Hopkins gave a "Hepatitis Debrief"' summarizing the vast quantity of data presented on new HCV therapies. Some of these drugs will first be used as add-ons to pegylated interferon/ribavirin, but all-oral, interferon-free regimens are on the horizon.
Gilead Science's nucleotide HCV polymerase inhibitor sofosbuvir was the biggest news in Washington, with results presented from several studies looking at different patient populations.
The latest findings from the ELECTRON trial showed that 12 weeks of sofosbuvir and the NS5A inhibitor ledipasvir plus either ribavirin or the non-nucleoside polymerase inhibitor GS-9669 produced sustained response rates of 100% for treatment-experienced genotype 1 patients with advanced liver fibrosis or cirrhosis. In the LONESTAR study, a fixed-dose combination of sofosbuvir/ledipasvir, with or without ribavirin, cured 95%-100% of treatment-naive people and prior non-responders to triple therapy with boceprevir or telaprevir.
"For years, people have said 'show us the cirrhotics, show us the null responders,'" Sulkowski said. We did see such data at this meeting, which revealed "dramatic advances" that "will change how we manage HCV."
Looking at people with HCV genotypes 2 or 3, sofosbuvir plus ribavirin led to sustained response for 93% of genotype 2 patients treated for 12 weeks and 85% of genotype 3 patients treated for 24 weeks in the VALENCE trial. This study underscores the growing realization that genotypes 2 and 3 -- traditionally classified together as "easier-to-treat" -- are actually quite different, with genotype 3 patients benefiting from more intensive therapy.
Turning to more difficult-to-treat patient groups, sofosbuvir plus ribavirin taken for 24 weeks cured 76% of previously untreated HIV/HCV coinfected people with genotype 1, while 12 weeks of treatment cured 88% and 67% of those with genotypes 2 or 3, respectively.
Other studies showed, for the first time, that sofosbuvir plus ribavirin taken before liver transplantation prevented HCV recurrence in 64% of patients, while the same combination taken after recurrence may offer a cure for transplant recipients.
Sofosbuvir is far from the only game in town. Researchers also presented promising data demonstrating cure rates in the 90%-100% range for all-oral combinations being developed by AbbVie (formerly Abbott), Boehringer Ingelheim, Bristol-Myers Squibb, and Merck.
The Phase 2 PEARL-I study showed that a dual combination of AbbVie's ritonavir-boosted protease inhibitor ABT-450 and NS5A inhibitor ABT-267 was potent enough to cure 95% of treatment-naive patients and 90% of prior null responders with easier-to-treat HCV subtype 1b and no cirrhosis. A similar combo, Merck's HCV protease inhibitor MK-5172 and NS5A inhibitor MK-8742, cured 100% of previously untreated non-cirrhotic participants in the C-WORTHY trial.
Like HCV genotypes 2 and 3, subtypes 1a and 1b are increasingly recognized as different entities. A Phase 3 Japanese study found that Bristol-Myers Squibb's protease inhibitor asunaprevir plus NS5A inhibitor daclatasvir cured 87% of previously untreated patients and 81% of prior non-responders with subtype 1b. This dual combination is less effective against 1a, but adding the polymerase inhibitor BMS-791325 in a triple regimen raised the sustained response rate to 91%.
A similar effect was seen with Boehringer Ingelheim's HCV protease inhibitor faldaprevir and polymerase inhibitor deleobuvir. This combination plus ribavirin cured 95% of treatment-naive genotype 1b patients, but only 17% of those with 1a. Substituting the NS5A inhibitor PPI-668 for ribavirin, however, increased the four-week post-treatment sustained response rate to 100% in an interim analysis.
Last month an FDA advisory committee recommended approval of sofosbuvir and Janssen's HCV protease inhibitor simeprevir, with full approval expected in early December. Both drugs were recommended in combination with pegylated interferon/ribavirin for genotype 1, and sofosbuvir also got the nod as part of an interferon-free regimen with ribavirin for genotypes 2 and 3.
Although it is unlikely to be included in the drugs' initial approved indications, data from the Phase 2 COSMOS study showed that the dual combination of sofosbuvir plus simeprevir, with or without ribavirin, for 12 weeks cured more than 90% of genotype 1 patients who did not respond to previous interferon-based treatment.
At an opening-day press conference, AASLD president Gregory Fitz was asked about the prospect of using these two drugs together "off-label" as an interferon-free regimen for people with genotype 1. He stressed that further studies are needed to determine which combinations work best together and what the correct doses are, but he acknowledged that on an individual level, "physicians will definitely do what they think is best for patients."
In a state-of-the-art lecture, Robert "Chip" Schooley, former chair of the AIDS Clinical Trials Group, compared the timelines for development of antiretroviral therapy for HIV and hepatitis C treatment. While the time from identification of the virus to the first effective targeted therapies was about twice as long for hepatitis C virus (1989-2011) as for HIV (1983-1996), the evolution from first-generation drugs to well-tolerated, easy-to-take next-generation options is proceeding faster for hepatitis C.
"We may be able to cure virtually everyone [with hepatitis C] who comes our way, without regard to the status of the host or the genotype of the virus," he predicted.
Access Is the Next Challenge
Over years or decades, chronic hepatitis C can lead to serious liver disease, including cirrhosis, hepatocellular carcinoma, and liver failure. Successful treatment can slow or halt liver disease progression and reduce the risk of liver cancer and death, but most patients remain untreated.
Deputy Assistant Secretary for Health Ronald Valdisseri, speaking in the same session with Sulkowski and Schooley, described a "cascade of care" similar to the well-known HIV cascade. Up to 3.9 million people in the U.S. are estimated to have chronic hepatitis C, about half of whom are aware they are infected. Among those who have been diagnosed, about 35% are referred to care, about 9% start treatment, and only about 5% are successfully treated and cured.
Recently updated guidelines from the Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force recommend that all "Baby Boomers" born between 1945 and 1965 should be screened for HCV at least once, regardless of risk factors. Many people who know they have hepatitis C have been anxiously awaiting new therapies and will likely start therapy once they can be treated without interferon for as little as 8 to 12 weeks. Expanded screening, more people taking advantage of treatment, and the higher cure rates of the new drugs together should contribute to improving what Valdiserri called a "sad bottom line."
In the era of interferon-based therapy, it was common practice to wait and see if people with hepatitis C progressed to moderate or worse fibrosis before subjecting them to treatment. Forthcoming therapies that are shorter, better tolerated, and more effective will change this calculation. But the cost of the new drugs could be a limiting factor.
Fitz predicted that new DAAs "could easily be $100,000 or more" for a course of treatment. "We'd like to think we could make decisions about what's best for the individual, but thinking about this on a population scale is daunting," he cautioned.
Echoing the same theme, Sulkowski said that once we are able to successfully treat all patients, delivery of DAAs to people with hepatitis C worldwide is the next charge. "Now the issue is access, and that will be a challenge," he concluded.
Liz Highleyman is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.
U.S. Food and Drug Administration to Review Two New Drugs for Hepatitis C as Virus Becomes Health Concern for Baby Boomers
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