Hepatitis C is a viral infection which, if left untreated, can lead to severe and potentially fatal liver damage. Existing treatments consist of a combination of drugs, usually ribavirin, pegylated interferon and a protease inhibitor, which together inhibit viral replication and enhance the body's immune response to eradicate the virus. These drugs can place a substantial burden on the patient, with complicated pill and injection regimens, which can last for up to 48 weeks, and unpleasant side-effects for some patients, including anemia, depression, and loss of appetite.
Although hepatitis C can be curable, different genetic strains of the virus respond differently to drug treatment, and a significant number of patients with genotype 1 hepatitis C (the most common strain of the virus in the United States and Europe) do not respond to existing treatments. Patients whose infection cannot be cured run the risk of sustaining substantial damage to their livers (such as cirrhosis), and patients in this group currently have no further treatment options.
A team of researchers from the Texas Liver Institute in San Antonio, Texas, USA, and Gilead Sciences, Inc., a biopharmaceutical company based in Foster City, California, USA, recruited 100 patients with genotype 1 hepatitis C virus who had either never received treatment (60 patients), or who had been treated unsuccessfully using existing drugs (40 patients). Of patients in the latter group, just over half (22, 55%) had cirrhosis.
All trial participants took a new combination pill consisting of the investigational drugs. Patients took the combination pill for either 8 weeks or 12 weeks, and some patients in the study also received ribavirin as part of their regimen. Participants were stratified into different groups according to whether they had previously received treatment for hepatitis C, their length of treatment, and whether they received the new combination pill alongside ribavirin or not.
At 12 weeks following the completion of therapy, nearly all (97 or 97%) of the patients in the study had achieved a sustained virological response (SVR) – essentially a functional cure for hepatitis C, where the virus is eliminated, and prevented from replicating.
Just under half of the patients in the study experienced at least one adverse event, with the highest rates observed in the groups of patients who were receiving ribavirin as part of their treatment regimen. No patient in any group discontinued treatment because of an adverse event.
According to Professor Eric Lawitz, of the Texas Liver Institute, who led the study, "To our knowledge, this trial is the first to report data for cirrhotic genotype 1 hepatitis C patients who did not respond to prior treatment with a protease inhibitor regimen, a population without treatment options at present. The results of this trial suggest that the fixed-dose combination of sofosbuvir and ledipasvir could offer patients a short, all-oral treatment that might be highly effective and safe in patients who tend not to respond well to existing therapies, including individuals with cirrhosis or black race, resistant strains of the virus, and those who have not responded to standard-of-care regimens that include protease inhibitors."
According to Professor Margaret Hellard, of the Burnet Institute, Melbourne, Australia, co-author of a linked Comment, "As a proof of concept study, [this] demonstrates very high response rates, regardless of the presence of cirrhosis, prior treatment failure, or [resistant] genotype. However, this was a small, single-centre study with only short follow-up, raising concerns about the representativeness of the sample and whether early clinical trial results can be easily generalized to real-world settings. Whilst giving cause for optimism, the full implications of these results need to be tempered for now."
Source
Abstract
Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial
The Lancet, Early Online Publication, 5 November 2013
doi:10.1016/S0140-6736(13)62121-2
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This article can be found in the following collections: Gastroenterology (Hepatobiliary disease); Infectious Diseases (Anti-infective therapy)
Summary
Background
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.
Methods
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.
Results
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.
Interpretation
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.
Funding
Gilead Sciences.
More information: www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62121-2/abstract
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