The final day of The
Liver Meeting 2013, the 64th annual meeting of the American
Association for the Study of Liver Diseases (AASLD) recently held in Washington, DC, featured an overview of the status
of therapy for hepatitis C virus (HCV), similarities between HCV and HIV, and a look towards
the future of treatment.
Mark
Sulkowski of Johns Hopkins presented a 'hepatitis debrief' summarising 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 (Incivo or Incivek) – increases sustained response
rates to about 60-70% and can shorten treatment to six months, but they come
with their own toxicities. "Clearly
there is a way to go," Sulkowski said.
Next-generation
DAAs have begun to fill this gap, as several of the drugs
described at The Liver Meeting offer cure rates upwards of 80-90% 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.
The US Food and Drug Administration advisory
panel this month approved Janssen/Medivir's HCV protease
inhibitor simeprevir (Olysio) and Gilead Science's nucleotide HCV
polymerase inhibitor sofosbuvir (Sovaldi). 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 not included in the drugs' initial approved indications, data
from the phase 2 COSMOS study showed 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 people with genotype 2 treated for
12 weeks and 85% for people with genotype 3 treated for 24 weeks in the VALENCE trial. This study underscores the growing
realisation that HCV genotypes 2 and 3 – traditionally classified together as
'easier to treat' – are in fact quite different, with genotype 3 patients
benefiting 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, 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 the past few years," also explored how
short a duration of treatment is feasible, finding that six 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 two 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% 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 people, who did not have cirrhosis, in the C-WORTHY trial.
Like HCV genotypes 2 and 3,
subtypes 1a and 1b are increasingly recognised 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
four-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 other
difficult-to-treat populations including people with HIV/HCV co-infection and liver
transplant recipients.
Sofosbuvir
plus ribavirin taken for 24 weeks cured 76% of previously untreated people with HIV/HCV
co-infection who had HCV genotype 1, in the PHOTON-1 trial, while 12 weeks of treatment cured 88% and 67% of those with
genotypes 2 or 3, respectively.
Two other studies showed, for the
first time, that sofosbuvir plus ribavirin taken before liver transplantation
prevented HCV recurrence in 64% of participants, 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 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 treatment 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 people 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."