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AASLD 2013: Liver Meeting Ends with Hepatitis C Debrief and the Future of Treatment

The final day of AASLD Liver Meeting, recently held in Washington, DC, featured an overview of the status of new hepatitis C therapies, similarities between HCV and HIV, and a look towards the future of hepatitis C treatment. The development of next-generation HCV drugs has been remarkably rapid and experts agree that it may soon be possible to cure all patients with hepatitis C, but access is likely to be a challenge.

Mark Sulkowski from Johns Hopkins presented a "hepatitis debrief" summarizing the vast quantity of data on new hepatitis C drugs presented at the meeting, saying he was "both impressed and inspired by breadth and depth of research."

The development of direct-acting antiviral agents (DAAs) has brought about a revolution in hepatitis C treatment. The old standard of care, pegylated interferon plus ribavirin, cured fewer than half of people with hard-to-treat HCV genotype 1 with a year of treatment fraught with side effects ranging from flu-like symptoms to depression.

Adding one of the first DAAs -- the HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek) -- increases sustained response rates to about 60%-70% and can shorten treatment to 6 months, but they come with their own toxicities. "Clearly there is a ways to go," Sulkowski said.

Next-generation DAAs have begun to fill this gap, as severalof the drugs described at the Liver Meeting offer cure rates upwards of 80%-90% percent with minimal side effects. 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.

A U.S. Food and Drug Administration advisory panel last month recommended approvalof Janssen/Medivir's HCV protease inhibitor simeprevir (formerly TMC435) and Gilead Science's nucleotide HCV polymerase inhibitor sofosbuvir (GS-7977). Both drugs were recommended in combination with pegylated interferon/ribavirin for people with genotype 1, and sofosbuvir was also recommended 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 studyshowed that a dual combination of sofosbuvir plus simeprevir for 12 weeks, with or without ribavirin, cured more than 90% of genotype 1 patients who did not respond to previous interferon-based therapy.

Looking at genotypes 2 and 3, sofosbuvir plus ribavirin led to 12-week post-treatment sustained virological response (SVR12) rates of 93% for genotype 2 patients treated for 12 weeks and 85% for genotype 3 patients treated for 24 weeks in the VALENCE trial. This study underscores the growing realization that HCV genotypes 2 and 3 -- traditionally classified together as "easier-to-treat" -- are in fact quite different, with genotype 3 patients benefitting from more intensive therapy.

Development of HCV NS5A replication complex inhibitors has expanded opportunities for interferon-free regimens that target different steps of the viral lifecycle. Though their mechanism of action is not fully understood, they appear to interfere with viral assembly. Several agents in this class, including daclatasvir (BMS-790052), ledipasvir (GS-5885), ABT-267, and MK-8742, have contributed to high cure rates in all-oral regimens with HCV protease or polymerase inhibitors.

The latest findings from the ELECTRON trial showed that 12 weeks of sofosbuvir and 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. ELECTRON, which Sulkowski said "has shaped if not transformed how we look at hepatitis C therapeutics over past few years," also explored how short a duration of treatment is feasible, finding that 6 weeks is too short even for easier-to-treat patients.

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. This trial "redefines how we think of treatment failure," according to Sulkowski. One of the 2 participants who relapsed and had multiple drug-resistance mutations was re-treated with sofosbuvir/ledipasvir/ribavirin for 24 weeks and went on to achieve a cure. "We would have predicted this wouldn’t work," he said, and "we need to learn more about treatment of DAA failures."

Researchers also presented promising data demonstrating cure rates in the 90%-100% percent range for all-oral combinations being developed by AbbVie, 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 ABT-267 was potent enough to cure 95% of treatment-naive patients and 90% of prior null responders with HCV subtype 1b and no cirrhosis. A similar combo, Merck's HCV protease inhibitor MK-5172 plus 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 (BMS-650032) plus 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 (BI 201335) and polymerase inhibitor deleobuvir (BI-207127). 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 4-week post-treatment sustained virological response (SVR4) rate to 100% in an interim analysis.

Sulkowski also described promising results from studies of interferon-free regimens for difficult-to-treat populations including HIV/HCV coinfected patients and liver transplant recipients.

Sofosbuvir plus ribavirin taken for 24 weeks cured 76% of previously untreated HIV/HCV coinfected people with genotype 1 in the PHOTON-1 trial, while 12 weeks of treatment cured 88% and 67% of those with genotypes 2 or 3, respectively.

Another pair of 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.

"One advantage of DAAs is the ability to treat hepatitis C patients who cannot tolerate interferon," Sulkowski said. "This itself is revolutionary."

Discussing the increasing proportion of liver transplants due to hepatocellular carcinoma (HCC) in people with hepatitis C, Sulkowski predicted that identifying and treating everyone with hepatitis C "could dramatically reduce the need for transplants." However, some people who already have liver damage still get HCC despite effective therapy, which "suggests it is better to treat before developing significant fibrosis."

In the era of interferon-based therapy, it has been common practice to wait and see if people with hepatitis C progress to moderate or worse fibrosis before subjecting them to 6 to 12 months of poorly tolerated 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. At an opening-day press conference, AASLD president Gregory Fitz suggested that the next-generation DAAs "could easily be $100,000 or more" for a course of treatment.

In summary, Sulkowski predicted that treatment with simeprevir or sofosbuvir plus pegylated interferon/ribavirin will soon become the new standard of care for genotype 1 hepatitis C. Following closely behind, multiple interferon-free regimens in late-stage development will offer high SVR rates even for prior null responders and patients with cirrhosis.

"For years, people have said 'show us the cirrhotics, show us the null responders'," he said. We did see such data at this meeting, revealing "dramatic advances" that "will change how we manage HCV." Delivery of DAAs to people with hepatitis C worldwide is the next charge, he concluded. "Now the issue is access, and that will be a challenge."

HIV Versus HCV

Robert "Chip" Schooley from the University of California at San Diego followed Sulkowski's talk with the annual Leon Schiff State-of-the-Art Lecture, comparing the evolution of hepatitis C treatment to that of antiretroviral therapy for HIV.

The conventional wisdom at the AASLD meeting 5 years ago held that small molecule DAAs were interesting, "but we'll always need a whiff of interferon." Infectious disease specialists assumed in 2008 that these molecules might work "but you'll have to use a bunch of them to cure anyone."

Summarizing the history of HIV treatment, Schooley -- former chair of the AIDS Clinical Trials Group -- recalled that HIV was identified as the cause of AIDS in 1983 and zidovudine (AZT, Retrovir) was the first drug to demonstrate a reduction in mortality in 1986. Treatment failure soon emerged, however, as the virus developed resistance to a single drug. HIV protease inhibitors -- the "first truly potent agents" -- came on the scene in 1995-1996. From then until the early 2000s, better-tolerated drugs were developed that could suppress HIV indefinitely. Today, many experts believe there is no reason to delay starting antiretroviral treatment and researchers are looking towards a cure.

HCV was first identified in 1989 and interferon-alfa/ribavirin combination therapy emerged in 1998. The year 2003 saw the first proof-of-concept clinical trials of HCV protease inhibitors, and boceprevir and telaprevir were approved in 2011.

While the time from identification of the virus to the first effective targeted therapies was about twice as long for HCV (1989-2011) as for HIV (1983-1996), the evolution from first-generation drugs to well-tolerated, easy-to-take, next-generation agents is proceeding more rapidly for hepatitis C -- and a widely applicable cure will come much sooner.

HCV replication is "more ambitious" than that of HIV, producing 100- to 3000-fold more new virus particles per day, and it is more prone to errors when copying its genetic material, leading to more resistance mutations, Schooley explained. On the other hand, HCV does not integrate its genetic material into host cell genes and it remains vulnerable to the innate immune response. Potent DAAs not only interfere with viral replication, but may also disrupt HCV's defenses, tipping the balance in the "tug of war" between the virus and the immune system.

Looking back at the conventional wisdom from 2008, Schooley said that both the hepatologists' and the infectious disease specialists' predictions were wrong: Small molecule DAAs do seem to work without interferon, and they're doing a better job than antiretrovirals.

In the near future, he predicted, "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."

11/21/13

References

MS Sulkowski. Hepatitis Debrief. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013.

RT Schooley Leon Schiff State-of-the-Art Lecture. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013.