Implementation of a decentralized hepatitis C care pathway for people who use drugs in Dutch addiction care. Study protocol for the Hepatitis C: chain of addiction care (CAC) project.

BACKGROUND: People who use drugs (PWUD) are at high risk for hepatitis C virus (HCV) infection and its complications. Given the high prevalence rate of HCV in PWUD, the World Health Organization (WHO) emphasizes PWUD as a target population for HCV elimination. The introduction of pangenotypic direct acting antivirals (DAAs) greatly simplifies HCV treatment, which encourages integration of HCV treatment in primary care. Facilitating low threshold HCV care for PWUD by implementing decentralized models is crucial for HCV elimination. AIMS: With this study we aim to (1) eliminate 90% of identified HCV infections in Dutch addiction care, using a decentralized PWUD-HCV care model, and (2) identify facilitators and barriers for successful implementation of the model using interviews. METHODS: We will perform a multicenter mixed-method study on HCV treatment in addiction care. In a prospective observational study we will examine HCV-related outcomes in PWUD receiving HCV treatment as part of addiction care. The primary outcome is viral elimination, defined as percentage of identified HCV positive patients cured with DAAs. In parallel, we will perform a qualitative study to explore facilitators and barriers for implementation of fully decentralized HCV-PWUD care. We will interview addiction care professionals and board members about their experience with HCV-care as part of addiction care. DISCUSSION: This study will show effectiveness of integration of HCV care within addiction care, and provide insight in facilitators and barriers to implement integrated HCV-addiction care. The results will provide recommendations for implementation and maintenance of the decentralized HCV pathway, which can facilitate scaling-up to contribute to reaching WHO HCV elimination goals. Trial registration NCT05401136.

Against All Odds? Addiction History Associated with Better Viral Hepatitis Care: A Dutch Nationwide Claims Data Study.

The elimination of viral hepatitis in target populations is crucial in reaching WHO viral hepatitis elimination goals. Several barriers for the treatment of viral hepatitis in people with addictive disorders have been identified, yet nationwide data on hepatitis healthcare utilization (HCU) in these patients are limited. We investigated whether a history of addictive disorder is associated with suboptimal hepatitis HCU, indicating failure to receive diagnostic care or treatment. We identified all newly referred viral hepatitis patients in the Netherlands between 2014 and 2019 by query of the Dutch national hospital claims database. Each patient's first year of HBV or HCV care activities was collected and clustered in two categories, 'optimal' or 'suboptimal' hepatitis HCU. Optimal HCU includes antiviral therapy. We tested the association between addiction history and HCU, adjusted for sex, age, migrant status, and comorbidity. In secondary analyses, we explored additional factors affecting hepatitis HCU. We included 10,513 incident HBV and HCV patients, with 13% having an addiction history. Only 47% of all patients achieved optimal hepatitis HCU. Addiction history was associated with less suboptimal HCU (adjusted OR = 0.73, 95% CI = 0.64-0.82). Migration background was associated with suboptimal HCU (OR = 1.62, 95% CI = 1.50-1.76). This study shows that addiction history is associated with higher viral hepatitis HCU; thus, this population performs better compared to non-addicted patients. However, less than 50% of all patients received optimal hepatitis care. This study highlights the need to improve hepatitis HCU in all patients, with a focus on migrant populations. Linkage to care in the addicted patients is not studied here and may be a remaining obstacle to be studied and improved to reach WHO viral hepatitis elimination goals.

Identification of the Best Direct-Acting Antiviral Regimen for Patients With Hepatitis C Virus Genotype 3 Infection: A Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective in the treatment of chronic hepatitis C virus (HCV) infection, although results for patients infected with genotype 3 are suboptimal. There are several regimens available, however, direct comparisons have not been made and are unlikely to occur. We aimed to identify the most effective DAA regimen for patients infected with HCV genotype 3 and to assess the role of ribavirin. METHODS: We conducted a systematic search of PubMed, Embase, and Web of Science databases through March 2016. We performed a Bayesian network meta-analysis using a random-effects model to indirectly compare regimens in patients with and without cirrhosis. We calculated mean estimated sustained virologic response (SVR) with 95% credible intervals (95% CrI) per regimen and effect of ribavirin as odds ratio. We focused on current recommended regimens and regimens under evaluation by regulatory authorities. RESULTS: Our search identified 2167 articles; 27 studies (comprising 3415 patients) were included. Among patients without cirrhosis, the greatest rates of SVR were estimated for those receiving sofosbuvir + velpatasvir with ribavirin (99%; 95% CrI, 98%-100%) and without ribavirin (97%; 95% CrI, 95%-99%), sofosbuvir + daclatasvir + ribavirin (96%; 95% CrI, 92%-98%), and sofosbuvir + peginterferon + ribavirin (95%; 95% CrI, 91%-98%), all for 12 weeks. Among patients with cirrhosis, the highest rates of SVR were estimated for those receiving sofosbuvir + velpatasvir for 24 weeks (96%; 95% CrI, 92%-99%), sofosbuvir + daclatasvir + ribavirin for 24 weeks (94%; 95% CrI, 87%-98%), and sofosbuvir + velpatasvir + ribavirin for 12 weeks (94%; 95% CrI, 86%-98%). Ribavirin increases efficacy in patients with and without cirrhosis (odds ratio, 2.6-4.5). CONCLUSIONS: An indirect comparison of DAA-based treatments, using Bayesian network meta-analysis, found regimens containing sofosbuvir and velpatasvir to be the best option for patients with HCV genotype 3 infection. Our analyses indicated that ribavirin significantly increases SVR rates and should be considered if tolerated.

Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study.

BACKGROUND: Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS: We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS: In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS: Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

High Risk of Infection During Triple Therapy with First-Generation Protease Inhibitors: A Nationwide Cohort Study.

BACKGROUND AND AIMS: Peginterferon (PegIFN) remains the backbone of therapy for chronic hepatitis C (CHC) in economically constrained regions. However, PegIFN may cause neutropenia and addition of a protease inhibitor can increase the likelihood of neutropenia. The aims of this study were to assess the occurrence of clinically relevant infections during first-generation protease inhibitor based therapy and its risk factors as well as the relation to treatment-induced neutropenia. METHODS: This multicenter (n=45) retrospective cohort study included CHC patients treated in the Netherlands. Based on absolute neutrophil count, categories of neutropenia were defined as: severe (<500/µL), moderate (500-750/µL) and mild (750-1500/µL). Likewise, infections were classified as severe (intravenous antibiotics/hospitalization) and moderate (anti-infective treatment). We assessed risk factors for infections using multivariable regression analysis with correction for multiple measurements. RESULTS: We included 467 CHC patients, 319 (68%) were male and 111 (24%) had cirrhosis. A total of 185 clinically relevant infections (34 severe) occurred in 145 patients (31%). During treatment 310 patients experienced neutropenia (34 severe). Multivariable analysis identified female sex (OR 1.7, 95%CI 1.2-2.5), chronic obstructive pulmonary disease (COPD) (OR 2.7, 95%CI 1.6- 4.5) and diabetes mellitus (OR 1.7, 95%CI 1.0-3.0) as risk factors for infections. Neutropenia at the previous visit was not associated with infection (univariable analysis: OR 0.9, 95%CI 0.6-1.3). CONCLUSION: This study shows that therapy with first generation protease inhibitors was complicated by an infection in 31% of patients. Not neutropenia, but female sex, COPD and diabetes mellitus were independent risk factors for infection. These patients should be monitored carefully once a PegIFN regimen is initiated.

The ARRIBA concept: adequate resorption of ribavirin.

BACKGROUND: Adequate ribavirin exposure is essential for optimal sustained virological response (SVR) rates in chronic HCV treatment. It has been proposed that the area under the concentration-time curve up to 4 h after intake of ribavirin (AUC0-4 h) of the first weight-based ribavirin dose should be ≥1.755 mg•h/l to guarantee the highest chance of SVR. Our ARRIBA concept comprises a test dose of ribavirin to select the optimal starting dose to achieve adequate exposure. This study aims to evaluate whether adequate exposure can be achieved after dose advice based on the AUC0-4 h of a single weight-based ribavirin test dose. METHODS: (Formerly) HCV-infected subjects received a single weight-based ribavirin test dose (<75 kg: 400 mg; ≥75 kg: 600 mg) and the AUC0-4 h was calculated. If ribavirin AUC0-4 h was ≥1.755 mg•h/l, subjects received the same dose 4 weeks later; if the AUC0-4 h was <1.755 mg•h/l, an adjusted dose was administered. The ribavirin AUC0-4 h was recorded again. The primary outcome was the proportion of subjects with an AUC0-4 h ≥1.755 mg•h/l after the second dose. RESULTS: A total of 26 subjects were included. The geometric mean (95% CI) ribavirin AUC0-4 h was 1.67 (1.44-1.92) mg•h/l with 9 subjects (35%) reaching the target AUC on day 1. Thus, on day 29, 17 subjects (65%) received an adjusted dose. The geometric mean (95% CI) AUC0-4 h increased to 1.90 (1.62-2.21) mg•h/l and then 16 subjects (62%) had an AUC0-4 h ≥1.755 mg•h/l, which is significantly higher than day 1 (P<0.05). CONCLUSIONS: Our ARRIBA concept of a ribavirin test dose, with dose adjustment if necessary, leads to an increased proportion of patients with an AUC≥1.755 mg•h/l compared to traditional weight-based ribavirin dosing.