HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Hepatitis C bio-behavioural surveys in people who inject drugs-a systematic review of sensitivity to the theoretical assumptions of respondent driven sampling

BackgroundNew, more effective and better-tolerated therapies for hepatitis C (HCV) have made the elimination of HCV a feasible objective. However, for this to be achieved, it is necessary to have a detailed understanding of HCV epidemiology in people who inject drugs (PWID).Respondent-driven sampling (RDS) can provide prevalence estimates in hidden populations such as PWID. The aims of this systematic review are to identify published studies that use RDS in PWID to measure the prevalence of HCV, and compare each study against the STROBE-RDS checklist to assess their sensitivity to the theoretical assumptions underlying RDS.MethodSearches were undertaken in accordance with PRISMA systematic review guidelines. Included studies were English language publications in peer-reviewed journals, which reported the use of RDS to recruit PWID to an HCV bio-behavioural survey. Data was extracted under three headings: (1) survey overview, (2) survey outcomes, and (3) reporting against selected STROBE-RDS criteria.ResultsThirty-one studies met the inclusion criteria. They varied in scale (range 1–15 survey sites) and the sample sizes achieved (range 81–1000 per survey site) but were consistent in describing the use of standard RDS methods including: seeds, coupons and recruitment incentives.Twenty-seven studies (87%) either calculated or reported the intention to calculate population prevalence estimates for HCV and two used RDS data to calculate the total population size of PWID. Detailed operational and analytical procedures and reporting against selected criteria from the STROBE-RDS checklist varied between studies. There were widespread indications that sampling did not meet the assumptions underlying RDS, which led to two studies being unable to report an estimated HCV population prevalence in at least one survey location.ConclusionRDS can be used to estimate a population prevalence of HCV in PWID and estimate the PWID population size. Accordingly, as a single instrument, it is a useful tool for guiding HCV elimination. However, future studies should report the operational conduct of each survey in accordance with the STROBE-RDS checklist to indicate sensitivity to the theoretical assumptions underlying the method.Systematic review registrationPROSPERO CRD4201501924

Prioritising Hepatitis C treatment in people with multiple injecting partners maximises prevention: a real-world network study

Objective To describe an injecting network of PWID living in an isolated community on the Isle of Wight (UK) and the results of a agent-based simulation, testing the effect of Hepatitis C (HCV) treatment on transmission. Method People who inject drugs (PWID) were identified via respondent driven sampling and recruited to a network and bio-behavioural survey. The injecting network they described formed the baseline population and potential transmission pathways in an agent-based simulation of HCV transmission and the effects of treatment over 12 months. Results On average each PWID had 2.6 injecting partners (range 0-14) and 137 were connected into a single component. HCV in the network was associated with a higher proportion of positive injecting partners (p=0.003) and increasing age (p=0.011). The treatment of well-connected PWID led to significantly fewer new infections of HCV than treating at random (10 vs. 7, p<0.001). In all scenarios less than one individual was re-infected. Conclusion In our model the preferential treatment of well-connected PWID maximised treatment as prevention. In the real-world setting, targeting treatment to actively injecting PWID, with multiple injecting partners may therefore represent the most efficient elimination strategy for HCV

Prioritising Hepatitis C treatment in people with multiple injecting partners maximises prevention : A real-world network study

Objective: To describe an injecting network of PWID living in an isolated community on the Isle of Wight (UK) and the results of a agent-based simulation, testing the effect of Hepatitis C (HCV) treatment on transmission. Method: People who inject drugs (PWID) were identified via respondent driven sampling and recruited to a network and bio-behavioural survey. The injecting network they described formed the baseline population and potential transmission pathways in an agent-based simulation of HCV transmission and the effects of treatment over 12 months. Results: On average each PWID had 2.6 injecting partners (range 0–14) and 137 were connected into a single component. HCV in the network was associated with a higher proportion of positive injecting partners (p = 0.003) and increasing age (p = 0.011). The treatment of well-connected PWID led to significantly fewer new infections of HCV than treating at random (10 vs. 7, p<0.001). In all scenarios less than one individual was re-infected. Conclusion: In our model the preferential treatment of well-connected PWID maximised treatment as prevention. In the real-world setting, targeting treatment to actively injecting PWID, with multiple injecting partners may therefore represent the most efficient elimination strategy for HCV

Integrating community pharmacy testing for hepatitis c with specialist care

Background: Many patients with hepatitis C virus (HCV) infection lie undiagnosed and a significant proportion of patients that have been identified are disengaged from specialist services. The Isle of Wight (IOW) typifies this issue, with an estimated 200 undiagnosed patients with HCV infection and a small number of known cases engaged with specialist services. Aim: To reduce the burden of undiagnosed HCV on the IOW and link new diagnoses directly to specialist care. Service development, design and implementation: Dry blood spot tests were undertaken at community pharmacies for HCV, hepatitis B, HIV and syphilis. Individuals testing positive for HCV RNA or hepatitis B surface antigen were automatically referred to the mainland hepatology service and were seen at a pharmacy 'point-of-diagnosis' consultation with the testing pharmacist and hepatologist. Pharmacy testing activity was compared with the local drug support centre (island recovery integrated service [IRIS]). Service outcomes: Over a period of nine months (September 2014 to May 2015), a total of 88 tests were performed at community pharmacies. Of these, 39 of the individuals tested reported injecting drug use as their main risk factor; 17 of these were not engaged at IRIS and were significantly less likely to have had a previous test (77% vs. 41%, P =0.04). During the same period at the IRIS centre, 34 tests were performed. A greater proportion of individuals had a history of injecting drug use (85%, P &lt;0.01) and were more likely to have had a test in the past three years (56%P, =0.07). Overall, 7% of pharmacy tests and 9% of IRIS tests were positive for HCV RNA (P =0.7); all pharmacy cases were seen at a point-of-diagnosis consultation with a hepatologist Conclusion: Pharmacy-based testing has the potential to reach at-risk individuals who are not tested for HCV elsewhere. When combined with integrated specialist referral, it has the potential to reduce the burden of undiagnosed HCV and engage new diagnoses directly with specialist care.</p

Prioritising Hepatitis C treatment in people with multiple injecting partners maximises prevention: A real-world network study

Objective: To describe an injecting network of PWID living in an isolated community on the Isle of Wight (UK) and the results of a agent-based simulation, testing the effect of Hepatitis C (HCV) treatment on transmission. Method: People who inject drugs (PWID) were identified via respondent driven sampling and recruited to a network and bio-behavioural survey. The injecting network they described formed the baseline population and potential transmission pathways in an agent-based simulation of HCV transmission and the effects of treatment over 12 months. Results: On average each PWID had 2.6 injecting partners (range 0–14) and 137 were connected into a single component. HCV in the network was associated with a higher proportion of positive injecting partners (p = 0.003) and increasing age (p = 0.011). The treatment of well-connected PWID led to significantly fewer new infections of HCV than treating at random (10 vs. 7, p<0.001). In all scenarios less than one individual was re-infected. Conclusion: In our model the preferential treatment of well-connected PWID maximised treatment as prevention. In the real-world setting, targeting treatment to actively injecting PWID, with multiple injecting partners may therefore represent the most efficient elimination strategy for HCV

Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions

AIMS: The primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon alpha-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone.METHODS: In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study.RESULTS: The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout half-lives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase half-lives was 5-7 h. IFN demonstrated an increase in bioavailability (approximately 2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2',5'-oligoadenylate synthetase (2'5'-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2'5'-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN--reductions in white cells, neutrophils and platelets; ribavirin--reduced haemoglobin) and characteristic adverse event profiles (IFN--headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin--headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation.CONCLUSIONS: There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.<br/

Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study

BackgroundChronic ulcerative colitis is a large bowel inflammatory condition associated with increased colorectal cancer risk over time, resulting in 1000 colectomies per year in the UK. Despite intensive colonoscopic surveillance, 50% of cases progress to invasive cancer before detection. Detecting early (precancer) molecular changes by analysing biopsies from routine colonoscopy should increase neoplasia detection.ObjectivesTo establish a deoxyribonucleic acid (DNA) marker panel associated with early neoplastic changes in ulcerative colitis patients. To develop the DNA methylation test for high-throughput analysis within the NHS. To prospectively evaluate the test within the existing colonoscopy surveillance programme.DesignModule 1 analysed 569 stored biopsies from neoplastic and non-neoplastic sites/patients using pyrosequencing for 11 genes that were previously reported to have altered promoter methylation associated with colitis-associated neoplasia. Classifiers were constructed to predict neoplasia based on gene combinations. Module 2 translated analysis to a NHS laboratory, assessing next-generation sequencing to increase speed and reduce cost. Module 3 applied the molecular classifiers within a prospective diagnostic accuracy study, in the existing ulcerative colitis surveillance programme. Comparisons were made between baseline and reference colonoscopies undertaken in a stratified patient sample 6–12 months later.SettingThirty-one UK hospitals.ParticipantsPatients with chronic ulcerative colitis, either for at least 10 years and extensive disease, or with primary sclerosing cholangitis.InterventionsAn optimised DNA methylation classifier tested on routine mucosal biopsies taken during colonoscopy.Main outcomeIdentifying ulcerative colitis patients with neoplasia.ResultsModule 1 selected five genes with specificity for neoplasia. The optimism-adjusted area under the receiver operating characteristic curve for neoplasia was 0.83 (95% confidence interval 0.79 to 0.88). Precancerous neoplasia showed a higher area under the receiver operating characteristic curve of 0.88 (95% confidence interval 0.84 to 0.92). Background mucosa had poorer discrimination (optimism-adjusted area under the receiver operating characteristic curve was 0.68, 95% confidence interval 0.62 to 0.73). Module 2 was unable to develop a robust next-generation sequencing assay because of the low amplification rates across all genes. In module 3, 818 patients underwent a baseline colonoscopy. The methylation assay (testing non-neoplastic mucosa) was compared with pathology assessments for neoplasia and showed a diagnostic odds ratio of 2.37 (95% confidence interval 1.46 to 3.82; p = 0.0002). The probability of dysplasia increased from 11.1% before testing to 17.7% after testing (95% confidence interval 13.0% to 23.2%), with a positive methylation result suggesting added value in neoplasia detection. To determine added value above colonoscopy alone, a second (reference) colonoscopy was performed in 193 patients without neoplasia. Although the test showed an increased number of patients with neoplasia associated with primary methylation changes, this failed to reach statistical significance (diagnostic odds ratio 3.93; 95% confidence interval 0.82 to 24.75; p = 0.09).LimitationsSince the inception of ENDCaP-C, technology has advanced to allow whole-genome or methylome testing to be performed.ConclusionsMethylation testing for chronic ulcerative colitis patients cannot be recommended based on this study. However, following up this cohort will reveal further neoplastic changes, indicating whether or not this test may be identifying a population at risk of future neoplasia and informing future surveillance programmes.Trial registrationCurrent Controlled Trials ISRCTN81826545.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 1. See the NIHR Journals Library website for further project information