Direct-acting antivirals for chronic hepatitis C.
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ABSTRACT:
SUBMITTER: Jakobsen JC
PROVIDER: S-EPMC6484383 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC6484376 | biostudies-literature
Project description:The development and evaluation of antiviral agents through carefully designed clinical trials over the last 25 years have heralded a new dawn in the treatment of patients chronically infected with the hepatitis B and C viruses, but not so for the D virus (HBV, HCV, and HDV). The introduction of direct acting antivirals (DDAs) for the treatment of HBV carriers has permitted the long-term use of these compounds for the continuous suppression of viral replication, whilst in the case of HCV in combination with the standard of care [SOC, pegylated interferon (PegIFN), and ribavirin] sustained virological responses (SVRs) have been achieved with increasing frequency. Progress in the case of HDV has been slow and lacking in significant breakthroughs.This paper aims to summarise the current state of play in treatment approaches for chonic viral hepatitis patients and future perspectives.
| S-EPMC3820491 | biostudies-literature
Project description:One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (?60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients.
| S-EPMC7172984 | biostudies-literature
Project description:BackgroundChronic hepatitis C (CHC) is associated with hepatic and extrahepatic complications, including cardiovascular disease (CVD). The effects of sustained virological response (SVR) and liver fibrosis on CVD risk are not well established.AimsWe aim to assess the dynamics of Fibrosis-4 (FIB-4) and Atherosclerotic Cardiovascular Disease 2013 (ASCVD) scores up to three years after direct acting antivirals (DAA) treatment and explore the time-dependent association between the two scores.MethodsWe included consecutive CHC patients treated with DAA and followed up with them for three years. Outcomes were changes from baseline (before DAA) in ASCVD and FIB-4 scores, measured at the end of treatment, 12-, 24-, and 36-months follow-up.ResultsIn total, 91 patients with CHC were finally included (median age: 66 years (IQR = 58-72 years); 43% females). Median follow-up was 2 years (1-3 years) and all patients reached SVR. The ASCVD score did not significantly change from baseline (Mean = 17.2%, 95% CI 14.1, 20.3), but the FIB-4 score significantly decreased at any time-point by an average of 0.8 (95% CI 0.78, 0.82, p < 0.001). Elevated FIB-4 scores at one (β = 1.16, p < 0.001) and three years (β = 2.52, p < 0.001) were associated with an increased ASCVD score. Clinically, two participants- with non-decreasing FIB-4 scores after treatment- had acute coronary syndrome at the end of treatment and one year follow-up, respectively.ConclusionsIn our study, we found that FIB-4 and ASCVD scores exhibited a positive correlation irrespective of time-point after treatment. Larger studies are essential to further investigate the utility of FIB-4 scores in cardiovascular risk assessment.
| S-EPMC9572655 | biostudies-literature
Project description:Background:Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) results in sustained virologic response (SVR) in > 90% of patients. However, some patients required retreatment with newer DAA options. Treatment was selected after consultation with a clinical pharmacy specialist. Methods:A retrospective chart review of patients at the West Palm Beach Veterans Affairs Medical Center (WPBVAMC) in Florida retreated from January 2015 to December 2019 was conducted. Data collected included HCV genotype, previous therapy, newly prescribed medications, and treatment outcomes. Results:Since 2015, > 900 patients have been treated at WPBVAMC, including 22 patients who had previously failed interferon combined with DAA regimens and 46 patients who needed retreatment after failure with an all-oral therapy. This review documents the outcomes of retreatment with DAA after initial failure to achieve SVR Of 28 patients treated with a boceprevir-based regimen, 10 ended in failure. All 10 were retreated, and all achieved SVR with ledipasvir/sofosbuvir. Of 53 patients treated with a sofosbuvir-based interferon regimen, 12 failed treatment. All 12 were retreated and all achieved SVR. Thirty patients were retreated after failure with an all-oral DAA. Of 27 tested, 21 achieved SVR. All patients who failed therapy again had cirrhosis. Conclusions:Veterans retreated with DAAs for HCV infection had a high success rate. Repeat failures of DAAs were rare, but cirrhosis seems to be common among these patients.
| S-EPMC7473721 | biostudies-literature
Project description:In the United States, chronic infection with the hepatitis C virus (HCV) affects an estimated 0.1-2% of the pediatric population, who are consequently at risk for major complications, including cirrhosis, hepatocellular carcinoma, and death. The current standard of treatment for chronic hepatitis C (CHC) in children is pegylated-interferon-alpha (PEG-IFN) in combination with ribavirin. PEG-IFN/ribavirin therapy is approved for children ages 3 and older; however, it is often held from use until adulthood because of its extensive list of potential side effects and high likelihood of causing adverse symptoms. While CHC is usually indolent in children and adolescents, immediately treating and curbing the spread of HCV before adulthood is important, as there can be transmission to other individuals via sexual activity and infected females can later vertically transmit the infection during pregnancy, the latter representing the most common means of transmission for children in the United States. The recent development of direct-acting antivirals has shown promising results in clinical trials for use in children and has dramatically increased the rates of sustained virological response in adults while improving side effect profiles as compared to interferon-based treatments. Given the usually indolent course of CHC in children, significant side effects of the currently-approved PEG-IFN/ribavirin therapy, and likely availability of all-oral interferon-free regimens for children within a few years, deferring treatment in clinically-stable children with CHC in anticipation of upcoming superior treatment modalities may be justified.
| S-EPMC5411358 | biostudies-literature
Project description:Background and aimTreatment of hepatitis C with direct-acting antiviral agents (DAA) has few side effects. Although pivotal studies suggested that DAA were safe in patients with psychiatric diseases who could not be treated with previous antiviral therapies, their effects on anxiety and depression have not yet been analysed in clinical practice. The aim of our study was to analyse anxiety and depression in the setting of DAA treatment in a clinical practice series.MethodsAll patients starting DAA treatment between November 1, 2014 and October 31, 2015 were eligible. Patients completed the Hospital Anxiety and Depression scale at different times during treatment. The results were plotted on line graphs and evaluated using a linear regression model with repeated measures.ResultsOne hundred and forty-five patients were included (11% with major psychiatric disorders; 32% on psychiatric treatment). Sustained virologic response (SVR) was achieved in 97.3% of cases. Anxiety and depression measures did not differ between time points. No differences between patients on psychiatric treatment or with advanced fibrosis or cirrhosis were found at any time point analysed.ConclusionDAA treatment had no impact on anxiety or depression during or after chronic hepatitis C infection treatment, even in high-risk patients with major psychiatric disorders.
| S-EPMC6300319 | biostudies-literature
Project description:BackgroundHCV-related extra-hepatic complications include peripheral neuropathies, with important prevalence and impact. A recent metanalysis of previous intervention trials concluded for insufficient data to support evidence-based treatments for this complication. In this longitudinal study, we assessed for the first time prevalence and outcome of neuropathy in a cohort of patients with chronic HCV, before and after direct-acting antiviral agent (DAA) treatment.MethodNinety-four patients (mean age 58.5 ± 9.9, infection duration 22.2 ± 6.3 years) without systemic and metabolic diseases, underwent neurological examination and electroneurography studies before (T0) and 10.4 ± 1.7 months after the end of DAA therapy (T1), and cryoglobulins (CG) assessment. Muscle strength was evaluated by Medical Research Council (MRC) score; neuropathic pain, sensory function, disability, quality of life were assessed by validated questionnaires (DN4, NPSI, SSS, INCAT and Euro-QoL).ResultsAt T0, sensory-motor neuropathy was detected in 22 patients (23%), reflexes were depressed in 32 (34%) with no association with infection duration, viral load, age, CG. Neuropathic pain (DN4 ≥4) was present in 37 patients (39%). At T1, out of the 22 patients with altered electroneurography, 3 had died or developed HCC, 4 showed normal electroneurography, and nerve amplitude parameters tended to improve in the whole group. Only 11 patients (12%) had depressed reflexes and 10 (11%) DN4 ≥4 (P < .05 compared to T0). Scores for MRC, questionnaires and Euro-QoL improved significantly (P < .05).ConclusionOur study confirms the high prevalence of clinical and subclinical peripheral sensory-motor neuropathy in patients with HCV infection and indicates improvement after eradication by DAA. These results support the need for larger intervention studies.
| S-EPMC8596576 | biostudies-literature
Project description:We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents.
| S-EPMC3252270 | biostudies-literature
Project description:PURPOSE:New direct-acting antiviral (DAA) drugs have revolutionized the treatment of hepatitis C in recent years. OBJECTIVE:Our objective was to analyse the cost effectiveness of combinations of different DAAs compared with ribavirin and peginterferon-α-2a, taking into account rebates from tender negotiations. METHODS:We used a compartmental model specifically developed for Norway to simulate hepatitis C and complications with and without different DAAs. All costs were based on Norwegian fees and estimates, estimating healthcare sector costs for the year 2016. We performed Monte Carlo simulations on uncertain input parameters to facilitate probabilistic sensitivity analyses. RESULTS:For patients diagnosed with genotype 1, the combination of paritaprevir, ritonavir, ombitasvir and dasabuvir was cost effective compared with eight other available alternatives, given a cost-effectiveness threshold of €70,000 per quality-adjusted life-year. For genotype 2, the combination of sofosbuvir and ribavirin was the most effective and cost-effective alternative for all patients. Among available alternatives for patients with genotype 3, sofosbuvir in combination with peginterferon and ribavirin was the most cost-effective alternative, although the combination of daclatasvir and sofosbuvir was somewhat more effective. CONCLUSIONS:For each of the hepatitis C genotypes 1, 2 and 3, there were combinations of DAAs that were cost effective in a Norwegian setting. As a result of recent tender negotiations in Norway, treating all diagnosed patients with hepatitis C with the most cost-effective DAAs will result in lower total expenditure on these medications compared with 2015.
| S-EPMC5906515 | biostudies-literature