ABSTRACT
BACKGROUND: The natural history and incidence of hepatocellular carcinoma (HCC) arising from indeterminate liver lesions are not well described. We aimed to define the incidence of HCC in a cohort of patients undergoing surveillance by magnetic resonance imaging (MRI) and estimate any associations with incident HCC. METHODS: We performed a retrospective follow-up study, identifying MRI scans in which indeterminate lesions had been reported between January 2006 and January 2017. Subsequent MRI scan reports were reviewed for incident HCC arising from indeterminate lesions, data were extracted from electronic patient records and survival analysis performed to estimate associations with baseline factors. RESULTS: One hundred and nine patients with indeterminate lesions on MRI were identified. HCC developed in 19 (17%) patients over mean follow up of 4.6 years. Univariate Cox proportional hazards analysis found incident HCC to be significantly associated with baseline low platelet count (hazard ratio (HR) = 7.3 (95% confidence intervals (CI) 2.1-24.9), high serum alpha-fetoprotein level (HR = 2.7 (95% CI 1.0-7.1)) and alcohol consumption above fourteen units weekly (HR = 3.1 (95% CI 1.1-8.7)). Multivariate analysis, however, found that only low platelet count was independently associated with HCC (HR = 5.5 (95% CI 0.6-5.1)). CONCLUSIONS: HCC arises in approximately one fifth of indeterminate liver lesions over 4.6 years and is associated with a low platelet count at the time of first diagnosis of an indeterminate lesion. Incidence of HCC was more common in people with viral hepatitis and in those consuming > 14 units of alcohol per week. Our data may be used to support a strategy of enhanced surveillance in patients with indeterminate lesions.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinoma, Hepatocellular/complications , Follow-Up Studies , Humans , Liver Neoplasms/complications , Magnetic Resonance Imaging/methods , Retrospective StudiesABSTRACT
BACKGROUND AND AIM: Mortality of alcohol-related liver disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non-invasive tests (NITs) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease, and in particular in ArLD, is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (Fibrosis 4 test [FIB4], Enhanced Liver Fibrosis [ELF] test, FibroScan, and FibroTest) in ArLD. METHODS: Applying systematic review methodology, we searched four databases from inception to May 2020. Inclusion/exclusion criteria were applied to search using Medical Subject Heading terms and keywords. The first and second reviewers independently screened results, extracted data, and performed risk-of-bias assessment using Quality in Prognosis Studies tool. RESULTS: Searches produced 25 088 articles. After initial screening, 1020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4 + FibroScan, and one on FibroTest + FIB4. Area under the receiver operating characteristic curves for outcome prediction ranged from 0.65 to 0.76 for FibroScan, 0.64 to 0.83 for FIB4, 0.69 to 0.79 for FibroTest, and 0.72 to 0.85 for ELF. Studies scored low-moderate risk of bias for most domains but high risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. CONCLUSIONS: This systematic review returned 11 papers, six of which were conference abstracts and one unpublished manuscript. While the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (area under the receiver operating characteristic curves >0.7 in each NIT category) and may add value to prognostication in clinical practice.
Subject(s)
Elasticity Imaging Techniques/methods , Liver Cirrhosis/diagnosis , Liver Diseases, Alcoholic/diagnosis , Liver Function Tests/methods , Female , Humans , Liver Cirrhosis/etiology , Liver Diseases, Alcoholic/complications , Male , Prognosis , ROC CurveABSTRACT
BACKGROUND: Chronic liver disease (CLD) is usually asymptomatic but earlier detection is critical to permit life-saving interventions for those at risk due to high alcohol consumption and increased body mass index (BMI). The aim of this study was to estimate the association between the Enhanced Liver Fibrosis (ELF) test and liver-related events (LRE) and its performance in predicting LRE in postmenopausal women with risk factors in a nested case-control study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). METHODS: In a cohort of 95,126 we performed a case-control study measuring ELF in blinded samples from 173 participants with self-reported high alcohol use and / or BMI ≥25 kg/m2 comprising all 58 cases who developed LRE and 115 controls matched for age, alcohol and BMI who did not develop LRE during median follow-up of 8.5 years. RESULTS: Using Cox regression at an ELF threshold of 10.51 hazard ratios (HR) for LRE were 4.88 (95% confidence interval (CI) 2.37-10.03) (unadjusted model) and 4.62 (95% CI 2.12-10.08) (adjusted for deprivation and self-reported hypertension, heart disease, hypercholesterolaemia and diabetes). At a threshold of 9.8 HR for LRE were 2.21 (95% CI 1.22-3.97) (unadjusted model) and 2.18 (95% CI 1.19-4.01) (adjusted). ELF was evaluated as a time dependent variable by generating time-dependent Cox models; HRs at an ELF threshold of 10.51 were 1.94 (95% CI 1.10-3.39) (unadjusted) and 2.05 (95% CI 1.16-3.64) (adjusted) and at a threshold of 9.8 HRs were 1.85 (95% CI 1.09-3.15) (unadjusted) and 1.80 (95% CI 1.04-3.13) (adjusted). Area under the receiver operating characteristic curve for recruitment ELF predicting LRE was 0.58 (95% CI 0.49-0.68), and for second subsequent ELF 0.61 (95% CI 0.52-0.71). CONCLUSION: This study demonstrates the association between ELF and CLD in postmenopausal women with risk factors for liver disease, creating the opportunity to intervene to reduce liver-related mortality and morbidity. Although larger studies are required, these results demonstrate the potential of ELF as a prognostic tool in health checks in primary care. TRIAL REGISTRATION: This study is nested in UKCTOCS. UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.
Subject(s)
Clinical Decision Rules , Health Status Indicators , Liver Diseases/diagnosis , Aged , Case-Control Studies , Female , Follow-Up Studies , Humans , Liver Cirrhosis/diagnosis , Liver Diseases/etiology , Liver Diseases/pathology , Middle Aged , Postmenopause , Prognosis , Retrospective Studies , Risk Factors , Self ReportABSTRACT
BACKGROUND & AIMS: The development of non-invasive liver fibrosis tests may enable earlier identification of patients with non-alcoholic fatty liver disease (NAFLD) requiring referral to secondary care. We developed and evaluated a pathway for the management of patients with NAFLD, aimed at improving the detection of cases of advanced fibrosis and cirrhosis, and avoiding unnecessary referrals. METHODS: This was a prospective longitudinal cohort study, with analyses performed before and after introduction of the pathway, and comparisons made to unexposed controls. We used a 2-step algorithm combining the use of Fibrosis-4 score followed by the ELF™ test if required. RESULTS: In total, 3,012 patients were analysed. Use of the pathway detected 5 times more cases of advanced fibrosis (Kleiner F3) and cirrhosis (odds ratio [OR]5.18;95%CI2.97-9.04; pâ¯<0.0001), while reducing unnecessary referrals from primary care to secondary care by 81% (OR0.193; 95%CI 0.111-0.337; pâ¯<0.0001). Although it was used for only 48% of referrals, significant benefits were observed in practices exposed to the pathway compared to those which were not, with unnecessary referrals falling by 77% (OR0.23; 95% CI0.658-0.082; pâ¯=â¯0.006) and a 4-fold improvement in detection of cases of advanced fibrosis and cirrhosis (OR4.32; 95% CI1.52-12.25; pâ¯=â¯0.006). Compared to referrals made before the introduction of the pathway, unnecessary referrals fell from 79/83 referrals (95.2%) to 107/152 (70.4%), representing an 88% reduction in unnecessary referrals when the pathway was followed (OR0.12; 95%CI0.042-0.349; pâ¯<0.0001). CONCLUSIONS: The use of non-invasive blood tests for liver fibrosis improves the detection of advanced fibrosis and cirrhosis, while reducing unnecessary referrals in patients with NAFLD. This strategy improves resource use and benefits patients. LAY SUMMARY: Non-alcoholic fatty liver disease effects up to 30% of the population but only a minority of cases develop liver disease. Our study has shown that established blood tests can be used in primary care to stratify patients with fatty liver disease, leading to a reduction in unnecessary referrals by 80% and greatly improving the detection of cases of advanced fibrosis and cirrhosis.
Subject(s)
Liver Cirrhosis/diagnosis , Liver Cirrhosis/etiology , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/therapy , Primary Health Care/methods , Referral and Consultation , Adult , Aged , Algorithms , Female , Hematologic Tests , Humans , Liver Function Tests , Longitudinal Studies , Male , Middle Aged , Prospective StudiesABSTRACT
UNLABELLED: The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). CONCLUSIONS: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care.
Subject(s)
Cholangitis/complications , End Stage Liver Disease/etiology , Ursodeoxycholic Acid/therapeutic use , Algorithms , Cholangitis/drug therapy , Female , Humans , Male , Middle Aged , Retrospective Studies , Risk AssessmentABSTRACT
BACKGROUND: Advancing fibrosis is regarded as the most important factor when stratifying patients with chronic hepatitis C for retreatment. GOALS: (1) To compare the performance of 10 biomarkers of fibrosis, including patented tests, among patients with chronic hepatitis C and treatment failure; and (2) to assess the impact on biomarker performance of using 2 different assays of hyaluronic acid (HA). STUDY: For 80 patients, liver histology (Metavir) was compared with biomarker scores using sera obtained within 6 months of liver biopsy (indirect biomarkers: AST:ALT ratio, APRI, Forns index, FIB-4, Fibrometer V3G; direct biomarkers: ELF, Fibrospect II, Hyaluronic acid-HA, Fibrometer V2G, Hepascore). Direct biomarker scores were calculated using 2 validated assays for HA (ELISA and radiometric). RESULTS: Using the ELISA assay for HA to calculate the direct panels, all 10 of the biomarkers exhibited comparable overall discriminatory performance (unweighted Obuchowski measure, ordROC 0.92-0.94, P-value>0.05) except AST:ALT ratio and APRI (ordROC 0.86-0.88, P-value<0.05). For the detection of moderate (F2-4) and advanced (F3-4) fibrosis, the AUROC of Fibrometer 2G were significantly higher than AST:ALT ratio and APRI but none of the other biomarkers. Good correlation was observed between the 2 HA assays (intraclass correlation coefficient=0.873) with the ELISA assay exhibiting superior diagnostic performance (ordROC 0.92 vs. 0.88, P-value=0.003). Importantly, the performance of many of the direct biomarkers at their diagnostic thresholds was heavily influenced by the choice of HA assay. CONCLUSIONS: Although many biomarkers exhibited good diagnostic performance for the detection of advancing fibrosis, our results indicate that diagnostic performance may be significantly affected by the selection of individual component assays.
Subject(s)
Biomarkers/blood , Hepatitis C, Chronic , Hyaluronic Acid/blood , Liver Cirrhosis/blood , Adolescent , Adult , Aged , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Sensitivity and Specificity , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND: We investigated the risk of chronic liver disease (CLD) due to alcohol consumption and body mass index (BMI) and the effects of their interaction in a prospective cohort study of women recruited to the UKCTOCS trial. METHODS: 95,126 post-menopausal women without documented CLD were stratified into 12 groups defined by combinations of BMI (normal, overweight, obese) and alcohol consumption (none, <1-15, 16-20 and ≥21 units/week), and followed for an average of 5.1 years. Hazard ratios (HR) were calculated for incident liver-related events (LRE). RESULTS: First LREs were reported in 325 (0.34%) participants. Compared to women with normal BMI, HR = 1.44 (95% CI; 1.10-1.87) in the overweight group and HR = 2.25 (95% CI; 1.70-2.97) in the obese group, adjusted for alcohol and potential confounders. Compared to those abstinent from alcohol, HR = 0.70 (95% CI; 0.55-0.88) for <1-15 units/week, 0.93 (95% CI; 0.50-1.73) for 16-20 units/week and 1.82 (95% CI; 0.97-3.39) for ≥21 units/week adjusted for BMI and potential confounders. Compared to women with normal BMI drinking no alcohol, HR for LRE in obese women consuming ≥21 units/week was 2.86 (95% CI; 0.67-12.42), 1.58 (95% CI; 0.96-2.61) for obese women drinking <1-15 units/week and 1.93 (95% CI; 0.66-5.62) in those with normal BMI consuming ≥21 units/week after adjustment for potential confounders. We found no significant interaction between BMI and alcohol. CONCLUSION: High BMI and alcohol consumption and abstinence are risk factors for CLD in post-menopausal women. However, BMI and alcohol do not demonstrate significant interaction in this group. TRIAL REGISTRATION: UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000.
Subject(s)
Alcohol Drinking/adverse effects , Body Mass Index , Ethanol/adverse effects , Liver Diseases/etiology , Obesity/complications , Aged , Chronic Disease , Female , Humans , Middle Aged , Ovarian Neoplasms/diagnosis , Overweight/complications , Postmenopause , Proportional Hazards Models , Prospective Studies , Risk Factors , United KingdomABSTRACT
UNLABELLED: Liver biopsy is the reference standard for the detection of nonalcoholic steatohepatitis (NASH) within nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify a biomarker of NASH in patients without significant fibrosis. In all, 172 patients from two centers with biopsy-proven NAFLD were included in this study. Eighty-four patients from a single center were included as a derivation cohort and 88 patients from a second center were included as a validation cohort. Serum samples were tested for candidate markers of fibrosis and inflammation alongside hematological and biochemical markers. Among patients without advanced fibrosis, terminal peptide of procollagen III (PIIINP) was the only marker found to be associated with a histological diagnosis of NASH in both cohorts. PIIINP also correlated with the total NAFLD activity score (NAS) and its constituent components (P < 0.001). Area under receiver operating characteristic curve (AUROC) for PIIINP in discriminating between NASH and simple steatosis (SS) was 0.77-0.82 in patients with F0-2 fibrosis and 0.82-0.84 in patients with F0-3 fibrosis. PIIINP was elevated in patients with advanced fibrosis, the overwhelming majority of whom had NASH. When incorporating patients with all degrees of fibrosis from both cohorts, PIIINP was able to discriminate between patients with SS and those with NASH or advanced fibrosis with AUROC 0.85-0.87. CONCLUSION: PIIINP discriminates between SS and NASH or advanced fibrosis. The use of a single biomarker in this context will be of clinical utility in detecting the minority of patients with NAFLD who have NASH or advanced fibrosis related to NASH.
Subject(s)
Fatty Liver/blood , Fatty Liver/diagnosis , Liver/pathology , Peptide Fragments/blood , Procollagen/blood , Adipokines/blood , Adult , Biomarkers/blood , Chitinase-3-Like Protein 1 , Collagen Type IV/blood , Female , Fibrosis , Humans , Hyaluronic Acid/blood , Keratin-18/blood , Lectins/blood , Male , Middle Aged , Multivariate Analysis , Tissue Inhibitor of Metalloproteinase-1/bloodABSTRACT
A 60-year-old male liver transplant recipient presented to his local hospital with left-sided partial seizures following a few days of generalised headache. He had undergone transplantation for primary sclerosing cholangitis 4 years earlier and maintained on tacrolimus monotherapy immunosuppression. He had no other comorbidities of note and worked as an arable farmer. At last follow-up, he had been well with preserved graft function and afternoon trough tacrolimus levels of 2-4 ng/mL. Over the preceding 4 weeks, he had been investigated locally for weight loss and a productive cough, where CT of the chest showed calcified mediastinal and hilar lymphadenopathy. Bronchoscopy samples were negative for acid-fast bacilli and he had been empirically treated for assumed community acquired pneumonia. Initial seizure management was with intravenous diazepam and phenytoin. On transfer to our centre, he was noted to be dysarthric with persisting 4/5 left upper limb weakness and nystagmus to all extremes of gaze. Blood tests were significant for mild anaemia (haemoglobin 90 g/L) and elevated C reactive protein (134 mg/L). The peripheral white cell count was 6.6×109/L. Biochemical liver graft function was normal and the 8am trough tacrolimus level was low at 2 ng/mL. CT head revealed bilateral ring enhancing cerebral lesions with surrounding vasogenic oedema but no mass effect. On MRI these exhibited restricted diffusion and marked perilesional oedema, suggestive of infection. Cerebrospinal fluid (CSF) analysis was as follows: white cell count <1/mm3, protein 0.57 g/L (normal range <45 g/L) and glucose 3 mmol/L (paired plasma glucose 4.8 mmol/L). Testing for virological causes via PCR, toxoplasma serology and blood and CSF cultures, including for tuberculosis, were all negative. Whole body positron emission tomography-CT demonstrated uptake in numerous peritoneal and intramuscular lesions as well as right-sided cervical lymphadenopathy, which was sampled with fine needle aspiration. Microscopy revealed a filamentous, beading and branching Gram-positive bacillus that was partially acid-fast, subsequently speciated as Nocardia farcinica.
ABSTRACT
At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a "wound healing" process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.
Subject(s)
Hepatitis C, Chronic/pathology , Liver Cirrhosis/immunology , Liver/pathology , Non-alcoholic Fatty Liver Disease/pathology , Adaptive Immunity , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Biopsy , Disease Models, Animal , Disease Progression , Drug Repositioning , Hepatic Stellate Cells/immunology , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/immunology , Hepatocytes/drug effects , Hepatocytes/immunology , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Immunity, Innate , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Inflammasomes/immunology , Inflammasomes/metabolism , Lipogenesis/immunology , Liver/drug effects , Liver/immunology , Liver/metabolism , Liver Cirrhosis/diagnosis , Liver Cirrhosis/pathology , Liver Cirrhosis/therapy , Myofibroblasts/transplantation , Non-alcoholic Fatty Liver Disease/immunology , Receptors, Pattern Recognition/immunology , Receptors, Pattern Recognition/metabolism , Treatment OutcomeABSTRACT
BACKGROUND: The enhanced liver fibrosis (ELF) blood test has recently been recommended by the National Institute for Health and Care Excellence to test for advanced fibrosis in nonalcoholic fatty liver disease. The ELF test involves calculating a score from the concentrations of serum biomarkers: tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), aminoterminal propeptide of procollagen type III (P3NP), and hyaluronic acid (HA). Blood samples for the ELF score are often acquired in primary care and may be stored before analysis. However, the effect of preanalytical storage on the ELF test is not known. METHODS: We conducted experiments to assess the stabilities of the ELF score, P3NP, HA, and TIMP-1 under medium- to long-term storage at -80 °C, repeated freeze-thawing, and refrigeration at 4 °C for days. RESULTS: Mean TIMP-1 concentrations increased during medium- to long-term storage (+16.5%) and refrigeration (+4.9%), but were stable during freeze-thawing. Mean P3NP concentrations were stable under medium- to long-term storage, but increased during refrigeration (+7.4%) and freeze-thawing (+9.3%). Mean HA concentrations decreased during medium- to long-term storage (-12.3%) but were stable during refrigeration and freeze-thawing. Despite changes in biomarker concentrations, the changes in the mean ELF score were not clinically significant and not >0.1 U (0.7%). CONCLUSIONS: The ELF score was stable, with no clinically significant changes under common storage conditions. These findings demonstrate that the ELF score is robust in situations where analysis may be delayed.
ABSTRACT
AIM: The utility of noninvasive serum markers to longitudinally monitor liver fibrosis is not established. METHODS: A total of 70 patients with chronic hepatitis C who had previously failed antiviral therapy were randomized to receive pegylated interferon with or without silymarin for 24 months. Enhanced Liver Fibrosis (ELF) tests (hyularonic acid, terminal peptide of procollagen III, tissue inhibitor of matrix metaloproteinase-1) were performed on patient sera obtained before, during and at the end of the study (0, 12, 24 months) and liver histology obtained before and at the end of the study. RESULTS: At 24 months, absolute changes in Ishak fibrosis stage and ELF ranged from -4 to +4 and from -2.41 to +2.68, respectively. Absolute changes in ELF at 12 months were significantly associated with changes in both ELF and histology at 24 months. A model combining both baseline ELF and change of ELF at 12 months could predict the 24-month ELF (R=0.609, P<1×10), a decrease in ELF at 24 months [area under the curve (AUC): 0.80-0.85] and an increase in ELF at 24 months (AUC: 0.81-0.85). Furthermore, a model combining both baseline histologic stage and ELF together with the change of ELF at 12 months could predict 24-month histology (R=0.601, P<1×10, AUC: 0.88-0.92), histologic fibrosis regression (AUC: 0.81-0.84) and progression (AUC: 0.86-0.91). CONCLUSION: Our observations suggest that a change in the serum marker ELF predicts changes in liver fibrosis over a longer period. These data support the use of ELF as a surrogate marker of liver fibrosis evolution in monitoring antifibrotic treatments, thus permitting 'response-guided' therapy by the early identification of patients who will benefit from prolonged treatment.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Liver Cirrhosis/drug therapy , Liver/drug effects , Polyethylene Glycols/therapeutic use , Silymarin/therapeutic use , Adolescent , Adult , Aged , Antiviral Agents/adverse effects , Area Under Curve , Austria , Biomarkers/blood , Biopsy , Drug Therapy, Combination , Female , Genotype , Germany , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/diagnosis , Humans , Hyaluronic Acid/blood , Interferon alpha-2 , Interferon-alpha/adverse effects , Liver/metabolism , Liver/pathology , Liver/virology , Liver Cirrhosis/blood , Liver Cirrhosis/diagnosis , Liver Cirrhosis/virology , Male , Middle Aged , Peptide Fragments/blood , Polyethylene Glycols/adverse effects , Predictive Value of Tests , Procollagen/blood , Prospective Studies , RNA, Viral/blood , ROC Curve , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Silymarin/adverse effects , Time Factors , Tissue Inhibitor of Metalloproteinase-1/blood , Treatment Outcome , Viral Load , Young AdultABSTRACT
The use of triple-therapy, pegylated-interferon, ribavirin and either of the first generation hepatitis C virus (HCV) protease inhibitors telaprevir or boceprevir, is the new standard of care for treating genotype 1 chronic HCV. Clinical trials have shown response rates of around 70-80%, but there is limited data from the use of this combination outside this setting. Through an expanded access programme, we treated 59 patients, treatment naïve and experienced, with triple therapy. Baseline factors predicting treatment response or failure during triple therapy phase were identified in 58 patients. Thirty seven (63.8%) of 58 patients had undetectable HCV RNA 12weeks after the end of treatment. Genotype 1a (p=0.053), null-response to previous treatment (p=0.034), the rate of viral load decline after 12weeks of previous interferon-based treatment (p=0.033) were all associated with triple-therapy failure. The most common cause of on-treatment failure for telaprevir-based regimens was the development of resistance-associated variants (RAVs) at amino acids 36 and/or 155 of HCV protease (p=0.027) whereas in boceprevir-based regimens mutations at amino acid 54 were significant (p=0.015). SVR12 rates approaching 64% were achieved using triple therapy outside the clinical trial setting, in a patient cohort that included cirrhotics.
Subject(s)
Antiviral Agents/therapeutic use , Drug Resistance, Viral , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Oligopeptides/therapeutic use , Proline/analogs & derivatives , Amino Acid Substitution , Drug Therapy, Combination/methods , Female , Hepacivirus/genetics , Humans , Interferon-alpha/therapeutic use , Male , Middle Aged , Mutation, Missense , Proline/therapeutic use , RNA, Viral/blood , RNA, Viral/genetics , Ribavirin/therapeutic use , Treatment Failure , Viral Load , Viral Nonstructural Proteins/geneticsABSTRACT
The primary aim of antiviral therapy for chronic hepatitis C (CHC) is the prevention of progressive disease. A response to interferon (IFN) treatment is associated with an improvement in all-cause mortality and liver-related mortality from hepatitis C. Unless contraindicated, patients with CHC are thus potential candidates for treatment. Improved response rates are observed in patients with HCV genotype 1 infection treated with first-generation protease inhibitors. However, treatment with current first-generation protease inhibitors and IFN is complex and can result in appreciable adverse effects. The advent of potent, pan-genotypic all-oral direct-acting antiviral (DAA) regimens necessitates a critical examination of the immediate application of PEG-IFN, ribavirin and DAA regimens in patients with CHC. Current guidelines and position statements do not make clear recommendations, and are behind the emerging data. Some aspects of the conundrums facing physicians and patients are summarized in this Review. Cirrhosis presents an immediate threat of disease, and ideally treatment should be targeted at those patients who have advancing or advanced disease; unfortunately, a disparity exists, as response rates are reduced in patients with cirrhosis and the risks of adverse events are increased. On balance, patients with mild disease could consider deferring treatment.
Subject(s)
Drug Therapy, Combination , Interferon-alpha , Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C/drug therapy , Humans , Interferon-alpha/therapeutic use , Ribavirin/therapeutic useABSTRACT
Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to affect sustained elimination of the virus (a sustained virological response [SVR]). The success and duration of therapy with interferon is dependent on HCV genotype. The current standard of care comprises combined treatment with pegylated interferon and ribavirin. Rates of SVR in patients with genotype 1 infection, the least responsive group, are less than 50%. Boceprevir is a ketoamide protease inhibitor that binds reversibly to the HCV nonstructural NS3 protease active site inhibiting intracellular viral replication. Phase III clinical studies have demonstrated that, in combination with the current standard of care, boceprevir significantly increases the SVR rate in both treatment-naive and previously treated patients with genotype 1 CHC. Both the US FDA and EMA have approved boceprevir for the treatment of genotype 1 CHC: the first directly-acting antiviral drug to be licensed for this indication. This article will review the pharmacology and pharmacodynamics of boceprevir, the efficacy and safety of the drug, and explore possible future developments in the management of CHC.
Subject(s)
Antiviral Agents , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Proline/analogs & derivatives , Protease Inhibitors , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Therapy, Combination , Hepacivirus/genetics , Hepatitis C, Chronic/virology , Humans , Interferon-alpha/administration & dosage , Interferon-alpha/therapeutic use , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/therapeutic use , Proline/administration & dosage , Proline/adverse effects , Proline/pharmacology , Proline/therapeutic use , Protease Inhibitors/administration & dosage , Protease Inhibitors/adverse effects , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Randomized Controlled Trials as Topic , Ribavirin/administration & dosage , Ribavirin/therapeutic use , Treatment OutcomeABSTRACT
INTRODUCTION: Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to effect sustained elimination of the virus (a sustained virological response, SVR). Prior to the development of direct-acting antiviral (DAA) agents, the standard of care (SOC) for CHC comprised combined treatment with pegylated interferon (PegIFN) and ribavirin (RBV). AREAS COVERED: TMC435 (Tibotec pharmaceuticals) is a macrocyclic non-covalent NS3/NS4A protease inhibitor (DAA) that is currently in Phase III clinical development. TMC435 is being developed in treatment regimens both with and without PegIFN and RBV. In Phase IIb clinical trials, the addition of TMC435 to current SOC significantly increased the SVR rate in both treatment-naive and experienced patients with CHC. It differs, however, from the other first-generation protease inhibitors in that it is administered once daily, has a different tolerability and resistance profile and has activity against CHC genotypes 1 - 6 with the exception of genotype 3. Furthermore, the addition of TMC435 to PegIFN/RBV appears to be able to significantly shorten treatment duration in the majority of patients. This article will review the pharmacology, pharmacodynamics, safety and efficacy of TMC435 by evaluating the preclinical and clinical studies to date. EXPERT OPINION: TMC435 is a 'second-wave' protease inhibitor that has the potential to play a pivotal role in the next phase of CHC treatment. The forthcoming results of Phase III trials involving TMC435 are awaited with interest.