Adherence to response-guided pegylated interferon and ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: the ACTIVATE study

Background: The aims of this analysis were to investigate treatment completion and adherence among people with ongoing injecting drug use or receiving opioid substitution therapy (OST) in a study of response-guided therapy for chronic HCV genotypes 2/3 infection. Methods: ACTIVATE was a multicenter clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b (PEG-IFN) and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Outcomes included treatment completion, PEG-IFN adherence, ribavirin adherence, and sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). Results: Among 93 people treated, 59% had recently injected drugs (past month), 77% were receiving OST and 56% injected drugs during therapy. Overall, 76% completed treatment. Mean on-treatment adherence to PEG-IFN and ribavirin were 98.2% and 94.6%. Overall, 6% of participants missed > 1 dose of PEG-IFN and 31% took <95% of their prescribed ribavirin., Higher treatment completion was observed among those receiving 12 vs. 24 weeks of treatment (97% vs. 46%, P < 0.001) while the proportion of participants with 95% on-treatment ribavirin adherence was similar between groups (67% vs. 72%, P = 0.664). Receiving 12 weeks of therapy was independently associated with treatment completion. No factors were associated with 95% RBV adherence. Neither recent injecting drug use at baseline nor during therapy was associated with treatment completion or adherence to ribavirin. In adjusted analysis, treatment completion was associated with SVR (aOR 23.9, 95% CI 2.9-193.8). Conclusions: This study demonstrated a high adherence to directly observed PEG-IFN and self-administered ribavirin among people with ongoing injecting drug use or receiving OST. These data also suggest that shortening therapy from 24 to 12 weeks can lead to improved treatment completion. Treatment completion was associated with improved response to therapy

Retreatment for hepatitis C virus direct-acting antiviral therapy virological failure in primary and tertiary settings: The REACH-C cohort

Virological failure occurs in a small proportion of people treated for hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapies. This study assessed retreatment for virological failure in a large real-world cohort. REACH-C is an Australian observational study (n = 10,843) evaluating treatment outcomes of sequential DAA initiations across 33 health services between March 2016 to June 2019. Virological failure retreatment data were collected until October 2020. Of 408 people with virological failure (81% male; median age 53; 38% cirrhosis; 56% genotype 3), 213 (54%) were retreated once; 15 were retreated twice. A range of genotype specific and pangenotypic DAAs were used to retreat virological failure in primary (n = 56) and tertiary (n = 157) settings. Following sofosbuvir/velpatasvir/voxilaprevir availability in 2019, the proportion retreated in primary care increased from 21% to 40% and median time to retreatment initiation declined from 294 to 152 days. Per protocol (PP) sustained virological response (SVR12) was similar for people retreated in primary and tertiary settings (80% vs 81%; p = 1.000). In regression analysis, sofosbuvir/velpatasvir/voxilaprevir (vs. other regimens) significantly decreased likelihood of second virological failure (PP SVR12 88% vs. 77%; adjusted odds ratio [AOR] 0.29; 95%CI 0.11–0.81); cirrhosis increased likelihood (PP SVR12 69% vs. 91%; AOR 4.26; 95%CI 1.64–11.09). Indigenous Australians had lower likelihood of retreatment initiation (AOR 0.36; 95%CI 0.15–0.81). Treatment setting and prescriber type were not associated with retreatment initiation or outcome. Virological failure can be effectively retreated in primary care. Expanded access to simplified retreatment regimens through decentralized models may increase retreatment uptake and reduce HCV-related mortality

Support and Assessment for Fall Emergency Referrals (SAFER 1): Cluster Randomised Trial of Computerised Clinical Decision Support for Paramedics

Objective: To evaluate effectiveness, safety and cost-effectiveness of Computerised Clinical Decision Support (CCDS) for paramedics attending older people who fall. Design: Cluster trial randomised by paramedic; modelling. Setting: 13 ambulance stations in two UK emergency ambulance services. Participants: 42 of 409 eligible paramedics, who attended 779 older patients for a reported fall. Interventions: Intervention paramedics received CCDS on Tablet computers to guide patient care. Control paramedics provided care as usual. One service had already installed electronic data capture. Main Outcome Measures: Effectiveness: patients referred to falls service, patient reported quality of life and satisfaction, processes of care. Safety: Further emergency contacts or death within one month. Cost-Effectiveness Costs and quality of life. We used findings from published Community Falls Prevention Trial to model cost-effectiveness. Results: 17 intervention paramedics used CCDS for 54 (12.4%) of 436 participants. They referred 42 (9.6%) to falls services, compared with 17 (5.0%) of 343 participants seen by 19 control paramedics [Odds ratio (OR) 2.04, 95% CI 1.12 to 3.72]. No adverse events were related to the intervention. Non-significant differences between groups included: subsequent emergency contacts (34.6% versus 29.1%; OR 1.27, 95% CI 0.93 to 1.72); quality of life (mean SF12 differences: MCS −0.74, 95% CI −2.83 to +1.28; PCS −0.13, 95% CI −1.65 to +1.39) and non-conveyance (42.0% versus 36.7%; OR 1.13, 95% CI 0.84 to 1.52). However ambulance job cycle time was 8.9 minutes longer for intervention patients (95% CI 2.3 to 15.3). Average net cost of implementing CCDS was £208 per patient with existing electronic data capture, and £308 without. Modelling estimated cost per quality-adjusted life-year at £15,000 with existing electronic data capture; and £22,200 without. Conclusions: Intervention paramedics referred twice as many participants to falls services with no difference in safety. CCDS is potentially cost-effective, especially with existing electronic data capture

Measuring routine childhood vaccination coverage in 204 countries and territories, 1980-2019 : a systematic analysis for the Global Burden of Disease Study 2020, Release 1

Background Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. Methods For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dosespecific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in countryreported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development. Findings By 2019, global coverage of third-dose DTP (DTP3; 81.6% [95% uncertainty interval 80.4-82 .7]) more than doubled from levels estimated in 1980 (39.9% [37.5-42.1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38.5% [35.4-41.3] in 1980 to 83.6% [82.3-84.8] in 2019). Third- dose polio vaccine (Pol3) coverage also increased, from 42.6% (41.4-44.1) in 1980 to 79.8% (78.4-81.1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56.8 million (52.6-60. 9) to 14.5 million (13.4-15.9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019. Interpretation After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing

Background & Aims: The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFN alpha-2a) induction therapy in treatment naive genotype 1 infection

Early on-treatment viral load and baseline METAVIR score: improved prediction of sustained virological response in HCV genotype 1 patients

Background: On-treatment HCV viral load during early therapy with pegylated interferon (PEG-IFN) and ribavirin is highly predictive of sustained virological response (SVR). We sought to provide further refinement of this prediction through an extensive evaluation of the effect of HCV viral loads at weeks 4, 8 and 12 on SVR, including analysis by liver disease stage grouping

Patterns and correlates of hepatitis C virus phylogenetic clustering among people living with HIV in Australia in the direct‐acting antiviral era: A molecular epidemiology study among participants in the CEASE cohort

Abstract Background and Aims In moving towards the elimination of hepatitis C virus (HCV) infection among people living with HIV, understanding HCV transmission patterns may provide insights to guide and evaluate interventions. In this study, we evaluated patterns of, and factors associated with HCV phylogenetic clustering among people living with HIV/HCV co‐infection in Australia in the direct‐acting antiviral era. Methods HCV RNA was extracted from dried blood spot (DBS) samples collected between 2014 and 2018 in the CEASE cohort study. The HCV Core‐E2 region was amplified by a polymerase chain reaction and Sanger sequenced. Maximum likelihood phylogenetic trees (1000 bootstrap replicates) were used to identify patterns of clustering (3% genetic distance threshold). Mixed‐effects logistic regression was used to determine correlates of phylogenetic clustering. Factors assessed were sexual risk behavior, education, injecting drug use, housing, employment, HIV viral load, age, sex, and sexuality. Results Phylogenetic trees were reconstructed for HCV subtype 1a (n = 139) and 3a (n = 63) sequences, with 29% (58/202) in a pair or cluster. Overall (n = 202), phylogenetic clustering was positively associated with younger age (under 40; adjusted odds ratio [aOR] 2.52, 95% confidence interval [CI] 1.20–5.29), and among gay and bisexual men (n = 168), was positively associated with younger age (aOR 2.61, 95% CI 1.10–6.19), higher education (aOR 2.58, 95% CI 1.09–6.13), and reporting high‐risk sexual behavior (aOR 3.94, 95% CI 1.31–11.84). During follow‐up, five reinfections were observed, but none were in phylogenetic clusters. Conclusion This study found a high proportion of phylogenetic relatedness, predominantly among younger people and gay and bisexual men reporting high‐risk sexual behavior. Despite this, few reinfections were observed, and reinfections demonstrated little relationship with known clusters. These findings highlight the importance of rapid HCV treatment initiation, together with monitoring of the phylogeny

Efficacy of response-guided directly observed pegylated interferon and self-administered ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: The ACTIVATE study

Background There are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. Methods ACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). Results Among 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. Conclusion This study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response

Efficacy of response-guided directly observed pegylated interferon and self-administered ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: The ACTIVATE study.

BACKGROUND There are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. METHODS ACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). RESULTS Among 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. CONCLUSION This study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response

Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.

BACKGROUND: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. METHODS: In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. FINDINGS: We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0.90 [SD 0.23]) was strongly associated with LDL-C concentration (p=1.4 x 10(-77); R(2)=0.11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0 [SD 0.21]) than did WHII controls (p=4.5 x 10(-16)), as did the mutation-negative Belgian patients (0.99 [0.19]; p=5.2 x 10(-20)). The score was also higher in UK (0.95 [0.20]; p=1.6 x 10(-5)) and Belgian (0.92 [0.20]; p=0.04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. INTERPRETATION: In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. FUNDING: British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry