Sofosbuvir-based interferon-free therapy for patients with HCV infection
26 July 2013
Tarik Asselah
Accepted Manuscript
International hepatology
Sofosbuvir-based interferon-free therapy for patients with HCV infection
Tarik Asselah PII: S0168-8278(13)00534-5
DOI:
http://dx.doi.org/10.1016/j.jhep.2013.07.023
Reference: JHEPAT 4806
To appear in: Journal of Hepatology
Received Date: 23 May 2013
Revised Date: 8 July 2013
Accepted Date: 10 July 2013
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COMMENTARY ON:
Nucleotide polymerase inhibitor sofosbuvir
plus ribavirin for hepatitis C.
Gane EJ,
Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey
MM. N Engl J Med. 2013 Jan 3;368(
1):34-44. doi: 10.1056/NEJMoa1208953.
Copyright ©
2013.
Abstract reprinted with permission from Massachusetts Medical Society.
http://www.ncbi.nlm.nih.gov/pubmed/23281974
Abstract
BACKGROUND: The standard treatment for hepatitis C virus (HCV) infection is
interferon, which is administered subcutaneously and can have troublesome side effects.
We evaluated sofosbuvir, an oral nucleotide
inhibitor of HCV polymerase, in interferon-
sparing and interferon-free regimens for the treatment of HCV infection.
METHODS: We provided open-label treatment to
eight groups of patients. A total of 40
previously untreated patients with HCV genotype
2 or 3 infection were randomly assigned to
four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus
ribavirin for 12 weeks. Three of these groups also
received peginterferon alfa-2a for 4, 8, or
12 weeks. Two additional groups of previously
untreated patients with HCV genotype 2 or 3
infection received sofosbuvir monotherapy fo
r 12 weeks or sofosbuvir plus peginterferon
alfa-2a and ribavirin for 8 weeks. Two groups
of patients with HCV genotype 1 infection
received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior
treatment and 25 with no previous treatment. We
report the rate of sustained virologic
response 24 weeks after therapy.
RESULTS: Of the 40 patients who underwent
randomization, all 10 (100%) who received
sofosbuvir plus ribavirin without interferon
and all 30 (100%) who received sofosbuvir plus
ribavirin for 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response
at 24 weeks. For the other patients with HCV
genotype 2 or 3 infection, all 10 (100%) who
received sofosbuvir plus peginterferon alfa
-2a and ribavirin for 8 weeks had a sustained
virologic response at 24 weeks, as did 6 of
10 (60%) who received sofosbuvir monotherapy.
Among patients with HCV genotype 1 infection, 21
of 25 previously untreated patients (84%)
and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response
at 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea,
rash, and anemia.
CONCLUSIONS: Sofosbuvir plus ribavirin for 12 weeks may be effective in previously
untreated patients with HCV genotype 1, 2, or
3 infection.
(Funded by Pharmasset and
Gilead Sciences; Clinical
Trials.gov number, NCT01260350)
© European Association for the Study of the Liver. Published by Elsevier B.V. All rights
reserved
For the treatment of HCV infection, several
direct-acting antivirals (DAAs), including NS3
protease inhibitors, nucleoside/nucleotide analogue and non-nucleoside inhibitors of the
RNA-dependent RNA polymerase, and NS5A inhibitors, are under development [1].
Among
them, Sofosbuvir is a
potent HCV-specific nucleotide analog (chain terminator). It is given
orally, once daily, without food effect. So far,
no safety signal in preclinical/clinical studies
has been observed with this compound. Sofosbuvir has a high
barrier to resistance with no
virologic breakthrough to date.
It has a pangenotypic antiviral effect, although it might be
less efficient in genotype 3 (G3).
The ELECTRON study goal was to evaluate the safety and efficacy of sofosbuvir as a
backbone of combination antiviral therapy in patients with chronic HCV genotype 1, 2 and 3
infections, including both treatment-naïve
and treatment-experienced patients [2]. The
design of the trials and the results are provided
in Fig. 1.
Fig. 1: Electron trial design and results [2].
ELECTRON is an open-label study with eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus ribavirin for12 weeks. Three of these groups also received PegIFNα-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus PegIFNα-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. The rate of sustained virologic response 24 weeks after therapy is reported.
Sofosbuvir combined with ribavirin
(RBV) for 12 weeks was associated with sustained virological response (SVR) in 100% of
G2/G3 HCV infected patients. For G1 HCV infected patients, 12 weeks sofosbuvir plus RBV
provided SVR12 in 84% of treatment-naïve,
but only in 10% of null responders.
For G2/3,
when sofosbuvir was given alone, SVR rate was 60%.
The authors concluded that sofosbuvir plus
RBV may be an effective treatment in all
previously untreated patients with G2 or G3
HCV
infections and also in the majority of G1
HCV naïve infected patients.
What have we learned and what are the questions raised?
First, can we predict relapse with early viral kinetics with sofosbuvir based regimen?
No,
unfortunately. Previous studies with pegylated-interferon (PegIFN) based therapy
demonstrated that early kinetics may help to predict SVR [4]. However, in this sofosbuvir
plus RBV trial, HCV RNA levels in all patients
declined rapidly after the initiation of treatment
(Fig. 2B).
Fig. 2. Mean change from baseline in hepatitis C virus (HCV) RNA level during treatmentAll patients with HCV genotype 2 or 3 infection completed the 12 weeks of treatment. All patients had an HCV RNA level below the limit of detection (i.e., <15 IU/ml) from week 4 until the end of treatment.
By week-2 of treatment, the majority of patients from all groups had an
undetectable level of HCV-RNA. By week-4 of treatment, all 95 patients in the study had an
undetectable level of HCV RNA, which was
maintained until the end of treatment.
Second, is RBV useful?
Yes. Results from the 10
patients with G2 or
G3 HCV infection who
received sofosbuvir alone strongly suggest a role for RBV in the maintenance of an antiviral
response. The exact mechanism by which RBV acts remains unknown.
Third, can we extrapolate these data to
phase 3 data or real-world practice?
No, we still have to be cautious
for several reasons: the number
of patients is limited; they
are selected as they have no cirrhosis, no comorbidities. We have to wait for more data, with
a larger number of patients, including difficult-to-cure patients with cirrhosis and previous
non-response.
For G1, since sofosbuvir and ribavirin is not
a reasonable option, two strategies have been
developed (1) 12 weeks sofosbuvir, PegIFN/RBV and (2) new IFN-free regimens with
sofosbuvir and ledipasvir (NS5A inhibitor).
Interestingly, several phase 3 studies with sofosbuvir based regimen have been published
since then.
The NEUTRINO trial was a single-group, open-label
study of sofosbuvir plus PegIFN/RBV in
327 patients infected with HCV genotype 1, 4, 5,
or 6 [5]. All patients received sofosbuvir,
PegIFN
α
-2a for 12 weeks. Most of the patients who were included in the study had HCV G1
(89%); 9% had G4, and 2% had G5 or 6. Sofosbuvir was given orally at a dose of 400 mg,
once a day, along with RBV, also
given orally in a dose bas
ed on body weight. Patients who
weighed less than 75 kg received 1000 mg/d, and heavier patients received 1200 mg/d.
Patients received PegIFN
α
-2a subcutaneously once a
week at a dose of 180
μ
g.
A total of 295 of the 327 patients (90%) reached
SVR after 12 weeks of
treatment. According
to the HCV genotype: 89% for patients with
G1 (92% for G1a and 82% for G1b) and 96%
(27/28) for those with G4 had SVR. The single patient with G5 and all six patients with G6 in
this trial had a SVR.
The FISSION trial was a randomized, open-label,
active-control study of sofosbuvir plus
RBV in patients with G2 or G3 HCV infection;
patients with the two genotypes were enrolled
in an approximately 1:3 ratio, respectively [5]. Patients were randomly assigned in a 1:1 ratio
to receive either 12 weeks of sofosbuvir plus RBV or 24 weeks of PegIFN/RBV. The doses
of sofosbuvir and RBV were the same as those administered in the Neutrino trial. The dose
of RBV for patients in the PegIFN/RBV
group was 800 mg daily. Sofosbuvir–RBV was
shown to be non-inferior to PegIFN/RBV. At
12 weeks, the rates of SVR for patients
receiving 12 weeks of sofosbuvir–RBV and those receiving 24 weeks of PegIFN/RBV were
each 67%. A SVR occurred in 97%
of patients with G2 and in 56% of those with G3 in the
group receiving sofosbuvir–RBV, as compared with response rates of 78% and 63%,
respectively, in the group receiving PegIFN/R
BV. Among patients with cirrhosis at baseline,
47% of those receiving sofosbuvir–RBV had
a SVR, as compared with 38% of those
receiving PegIFN/RBV.
The POSITRON trial was a double blinded,
placebo-controlled study that compared 12
weeks of treatment with sofosbuvir and RBV with matching placebo in patients who had
previously discontinued IFN
-therapy owing to unacceptable adverse events, who had a
concurrent medical condition precluding therapy with an IFN-containing regimen, or who had
decided against treatment with an IFN-containing regimen [6]. The most common reasons
that IFN treatment was not an option were clinically significant psychiatric disorders (in 57%
of patients) and autoimmune disorders (in 19%).
The rate of SVR at 12 weeks after treatment was 78% among patients receiving sofosbuvir-RBV, as compared with 0% among those receiving placebo (p<0.001). Among patients who received sofosbuvir-RBV, 93% of patients with G2 HCV infection had a SVR, as compared with 61% of those with G3 HCV infection. Likewise, 81% of patients without cirrhosis (92% of patients with G2 HCV infection and 68% of those with G3 HCV infection) had a SVR, as compared with 61% of patients with cirrhosis (94% of patients with G2 HCV infection and21% of those with G3 HCV infection).
The FUSION study was a blinded, active-control study involving patients who had not had a response to prior treatment with an IFN-containing regimen. Approximately 75% of the previously treated patients enrolled had either virologic breakthrough during the prior treatment or virologic relapse afterward; the remainder did not have a response. The rates of SVR achieved were superior to the historical control rate of 25%, with rates of 50% in the12-week group and 73% in the 16-week group (p <0.001 for each comparison). Rates of SVR between the groups showed that patients receiving 16 weeks of treatment had a significantly higher rate of SVR than patients receiving 12 weeks of treatment (p <0.001).
The rates of SVR among patients with G2 HCV infection who received 12 weeks of treatment and those who received 16 weeks of treatment were 86% and 94%, respectively, as compared with 30% and 62% for 12 and 16 weeks of treatment, respectively, among patients with G3 HCV infection. Cirrhosis was associated with a decreased rate of SVR, particularly among patients with G3HCV infection who received 12 weeks of treatment. Among patients with cirrhosis who received 12 weeks of treatment, the rate of SVR was 31% (60% with G2 HCV infection and 19% with G3 HCV infection), as compared with 61% among patients without cirrhosis (96% with G2 HCV infection and 37% with G3 HCV infection). Among patients with cirrhosis who received 16 weeks of treatment, the rate of SVR was 66% (78% with G2 HCV infection and 61% with G3 HCV infection) as compared with 76% among patients without cirrhosis (100% with G2 HCV infection and 63% with G3 HCV infection).
So can we summarize these data?
Yes, we can (Table 1). Summary
What are the key messages?
First, for G1 HCV naïve patients, sofosbuvir with PegIFN-RBV triple therapy appears a reasonable option. Of course, we will need to increase the number of patients with cirrhosis; and also data from genotype 1 experienced patients. There are ongoing phase 3 studies to investigate the efficacy and safety of sofosbuvir/ledipasvir fixed-dose combination with orwithout RBV for 8 or 12 weeks in treatment-naive G1 HCV chronic infection. Ledipasvir is anNS5A replication complex inhibitor ledipasvir (previously GS-5885).
Second, for G4 naïve patients, the data are excellent but limited (n = 28 patients) and we need larger studies for this specific G4 HCV population. There is a major medical need since standard of care remains PegIFN-RBV for 48 weeks with low SVR in “difficult-to-cure” patients population (IL28B non CC; patients with cirrhosis, experienced patients, etc;..).
We urge for studies in G4 HCV, naïve but also experienced patients.
Third, for G2 HCV naïve patients, sofosbuvir-RBV provide excellent results. We have to recall obvious evidence: G2 HCV is not G3, and we need separate studies. In past PegIFN/RBV dual therapy, for statistical issues, HCV G1 and G4, and HCV G2 and G3,were respectively pooled. For DAAs, we need individual study for each genotype. For G2HCV treatment experienced and cirrhosis, we need more data.
Four, data were disappointing regarding G3 HCV naïve patients, in particular those with cirrhosis. The question is how to treat HCV G3 infected patients in the near future. There will be several options:
(1) PegIFN plus RBV, with satisfactory results, but with IFN side effects.
(2) Sofasbuvir plus RBV for 16 weeks: (better tolerated, possible in case of IFN contraindication, but not better than PegIFN plus RBV, and even worse in cirrhotics).
(3) Sofosbuvir plus RBV for 24 weeks; however, SVR results will be given by the ongoing VALENCE study
(4) Triple therapy (Sofosbuvir plus PegIFN-RBV) with a short duration of 12 weeks, using the neutrino regimen, but without data with G3!
Moreover, it is believed that clinical trials provide best evidence when they are randomized to controlled arms with large number of patients [7]. Several of the trials discussed here lack controlled arms or large number of patients.
It may be argue that controlled arms are not necessary when they expose patients to side effects. Furthermore, we need data for «difficult-to-cure» patients, those with cirrhosis, previous non response, comorbidities, etc...
Impressive data have been reported with sofosbuvir based therapy, with high SVR rates and a favorable safety profile so far. A pilot study demonstrated that addition of ledipasvir increased efficacy of sofosbuvir plus RBV, without additional safety issues, and without virologic failures. Gilead recently initiated the first Phase 3 trial (ION-I) evaluating a fixed-dose combination of sofosbuvir and lepidasvir in treatment-naïve G1 HCV infected patients. This four-arm study is evaluating the fixed-dose combination with and without RBV for 12-and 24-week durations in 800 patients, 20 percent of whom have evidence of cirrhosis. Finally, there is a realistic hope for patients with HCV infection, since several IFN-free trials are ongoing with promising early data [8-10].
We do hope that the majority of patients with HCV infection will become «easy-to-cure», and there will be increase in access to treatment.
Conflict of interest
Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Janssen,Gilead, Roche and MSD.
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Hepatitis C particles (yellow) infect liver cells, causing disease and cancer.
