Interferon-based treatment is not suitable for many patients with hepatitis C virus
(HCV) infection because of contraindications such as psychiatric illness, and a high
burden of adverse events. We assessed the efficacy and safety of an interferon-free
regimen--a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir
(400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin--in
patients with genotype-1 hepatitis C infection who were treatment-naive or previously
treated with a protease-inhibitor regimen.
For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection
at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used
a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype
[1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus
ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks
(group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly
allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients
who previously had virological failure after receiving a protease inhibitor regimen
to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir
and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated
cirrhosis. The primary endpoint was sustained virological response 12 weeks after
treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov,
number NCT01329978.
In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75-100) in group
1, by 21 (100%) of 21 patients (84-100) in group 2, and by 18 (95%) of 19 patients
(74-100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74-100)
in group 4 and by all 21 (100%) of 21 patients (84-100) in group 5. Two patients had
viral relapse; one patient was lost to follow-up after achieving sustained virological
response 8 weeks after treatment. The most common adverse events were nausea, anaemia,
upper respiratory tract infection, and headache. One patient in group five had a serious
adverse event of anaemia, thought to be related to ribavirin treatment.
These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone
or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective
of treatment history or the presence of compensated cirrhosis. Further clinical trials
are needed to establish the best treatment duration and to further assess the contribution
of ribavirin.
Gilead Sciences.
Copyright © 2014 Elsevier Ltd. All rights reserved.