therapy using an all-oral regimen of three direct-acting antivirals cured a
majority of easier-to-treat genotype 1b hepatitis C patients in just 3 weeks,
according to results from the small SODAPI pilot study, presented in a
late-breaking poster at the 2015 AASLD Liver Meeting last month in San Francisco.
Further research will be needed to see if these promising results are borne out
in larger patient populations.
antiviral agents (DAAs) used in interferon-free regimens have already brought
about a revolution in treatment for chronic hepatitis C, but researchers
continue to search for therapies that are more effective, easier to use and
less expensive. Targeting multiple steps of the hepatitis C virus (HCV)
lifecycle could potentially shorten therapy and reduce the risk of viral
rebound and drug resistance.
Treatment using currently
approved hepatitis C regimens, including Gilead Science's sofosbuvir/ledipasvir
(Harvoni) and AbbVie's paritaprevir-based Viekirax/Exviera,
is typically indicated for 12 weeks, although sofosbuvir/ledipasvir for 8 weeks
works well for previously untreated genotype 1 patients without cirrhosis.
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
- rapid virological response (RVR)
An undetectable hepatitis C RNA viral load within 4 weeks of starting treatment. An extended rapid virological response (eRVR) is when viral load is undetectable within 4 weeks and remains undetectable until at least week 12.
A few studies have looked at multidrug regimens taken
for 6 weeks or less. The C-SWIFT study, which tested sofosbuvir plus Merck's grazoprevir and elbasvir, found that nearly 90% of
treatment-naive people without cirrhosis could be cured in 6 weeks, but only
about a third of those treated for 4 weeks achieved sustained response.
Likewise in the US National Institutes of Health SYNERGY study, sofosbuvir/ledipasvir plus one or two other Gilead
DAAs had a cure rate of just 20 to 40% with 4 weeks of therapy.
George Lau of Humanity and
Heath Medical Centre in Hong Kong and an international team of colleagues
evaluated a three-drug DAA regimen using response-guided therapy to see if
patients who responded rapidly at the outset of treatment could be cured in
just 3 weeks.
Rapid virological response (previously usually defined
as response at treatment week 4) was used in the interferon era to predict
which patients were unlikely to be cured and therefore could be taken off the
poorly tolerated therapy, or to guide treatment duration using
interferon/ribavirin plus the first-generation HCV protease inhibitors
boceprevir (Victrelis) or telaprevir
(Incivo). But so far it has not been
widely used for interferon-free DAA treatment.
The open-label SODAPI study
included 26 Chinese patients with HCV subtype 1b, which is easier to treat than
subtype 1a. A majority were women and the median age was about 37 years. Just
over half had been previously treated for hepatitis C. Most had absent or mild
liver fibrosis (stage F0-F1) and none had cirrhosis. About two-thirds
had the favourable IL28B 'CC' gene pattern associated with good interferon
response. At baseline the mean HCV
viral load was approximately 6.5 log IU/ml.
Participants were randomly assigned to receive three-drug
regimens consisting of the NS5B nucleotide polymerase inhibitor sofosbuvir
(sold separately as Sovaldi), one of
the NS5A replication complex inhibitors ledipasvir or daclatasvir (Daklinza), and one of the HCV NS3/4A
protease inhibitors asunaprevir (Sunvepra)
or simeprevir (Olysio).
- Group 1: sofosbuvir/ledipasvir and asunaprevir
(n = 12)
- Group 2: sofosbuvir, daclatasvir and simeprevir
(n = 6)
- Group 3: sofosbuvir, daclatasvir and asunaprevir
(n = 8)
Participants with rapid virological response (RVR),
defined as HCV RNA < 500 IU/ml by day 2, stopped treatment after 3 weeks,
while the remainder continued for 8 to 12 weeks. The primary endpoint was
sustained virological response, or continued undetectable HCV viral load
(< 25 IU/ml) at 12 weeks post-treatment (SVR12).
Overall, 18 participants (67%) – six in each treatment
arm – experienced RVR at day 2 of therapy. By week 3 all participants in all
treatment arms had HCV RNA below the limit of quantification. All 18 people who
had RVR at day 2 and completed treatment at 3 weeks achieved SVR12.
People who achieved RVR had lower baseline viral load
on average than those without RVR (about 6 vs 7 log IU/m), and were less likely to have
high baseline viral load (55% vs 100%, respectively) – these were the only
significant predictors. People with prior treatment experience and those with
more fibrosis appeared somewhat less likely to achieve RVR, but the subgroup
numbers were small and differences did not reach statistical significance.
Treatment was generally well-tolerated with no serious
adverse events or treatment discontinuations.
Compared to standard treatment using
sofosbuvir/ledipasvir for 8 weeks or sofosbuvir plus daclatasvir for 12 weeks,
the researchers calculated that the 3-week regimen could save between US$37,454
and US$107,045 per patient.
"In this proof-of-concept study, all (100%)
non-cirrhotic chronic hepatitis C genotype 1b Chinese treated with triple DAAs
[who had] RVR by day 2 achieve SVR12," the researchers concluded. These
results, they added, warrant further study of "DAAs with high potency and
non-overlapping resistance profiles tailored to specific characteristics of the
subjects and viruses."
These results suggest that while 4 weeks of treatment
does not work well in general, shortening therapy even down to 3 weeks may be
adequate for some easy-to-treat patients, and that early response can help
determine who should continue therapy for the usual 8- or 12-week course. The
findings also indicate that people with HCV subtype 1b – most people in C-SWIFT
and SYNERGY had 1a – may be the best candidates for abbreviated therapy.
Senior investigator Raymond Schinazi of Emory
University – one of the co-discoverers of sofosbuvir – suggested that the fact
that the drugs used in SODAPI are produced by different companies has hampered
research looking at cross-company combinations. "I want to show these companies that they should have done this study a
long time ago themselves," Schinazi told Jon Cohen of Science
Magazine. "When you put the best drugs together,
you get fabulous results."