Impact of Recent Drug Use on the Efficacy of Elbasvir/Grazoprevir for HCV-infected People on Opioid Agonist Therapy

Juan Macías; Francisco Téllez; Ignacio de los Santos; Luis E. Morano; Dolores Merino; Rafael Granados; Francisco Vera-Mendez; Alejandro González-Serna; Esther Campo-Moneo; Lucio García-Fraile; Federico García; Luis M. Real; Juan A. Pineda

Disclosures

J Viral Hepat. 2021;28(6):878-886. 

In This Article

Patients and Methods

Design and Patients

The HEPAVIR-DAA cohort (NCT02057003), which includes HIV/HCV-coinfected patients, and the GEHEP-MONO cohort (NCT02333292), which recruits HCV-monoinfected individuals, are ongoing prospective multicenter cohorts of patients receiving DAA combinations prescribed in clinical practice, outside clinical trials. Patients included in these cohorts with chronic genotype 1 or 4 HCV infection who started EBR/GZR were included in the present analysis. Patients taking at least one dose of the combination were eligible. Individuals were excluded if they underwent a liver transplant before reaching the date of SVR12 evaluation.

Medications and Follow-up

Elbasvir 50 mg plus grazoprevir 100 mg, as fixed-dose two drug combination (Zepatier®), was used as prescription medication to treat HCV infection in routine clinical practice in Spain according to national guidelines.[10] According to these guidelines, the standard duration of the combination EBR/GZR is 12 weeks. EBR/GZR may be combined with RBV and used during 16 weeks under certain unfavourable circumstances. The decision to treat and the choice of treatment, including treatment duration and the use or not of concomitant ribavirin, were entirely at the discretion of the treating physician.

The efficacy of therapy was assessed by the SVR12 rate. SVR12 was defined as the achievement of plasma HCV RNA below the limit of detection 12 weeks after the end of therapy (SVR12) with EBR/GZR. Reinfections were differentiated from relapses by genotype switch or by phylogenetic analysis if there was no genotype change. As SVR12 is the primary end-point, reinfections were assessed at 12 weeks after the end of therapy. In addition, for patients reaching 24 weeks after therapy, reinfections at SVR24 were also evaluated.

Classification of Patients According to Drug use

Drug use was assessed by physician-driven interview during clinical visits, and thus, it was self-reported. We considered as PWID all individuals with current or past injecting drug use. PWID were considered as recent drug users if they referred drug use within 3 months before treatment commencement. People who reported ever-injecting drug use and recent drug users were identified by retrospective chart review of databases and clinical records. Individuals using cannabis alone were not classified as active drug users. OAT is managed by drug addiction facilities in Spain. Data on OAT use among patients included in the cohorts are prospectively recorded.

Laboratory Determinations

Among patients with HCV viremia reemergence after finishing the scheduled duration of therapy, the NS5B polymerase, NS3 protease and/or NS5A protein were Sanger sequenced using in house developed assays[11] on samples taken both at failure and baseline time points, where available. To discriminate reinfection from relapse, we used at least two regions from HCV genome and, if reinfection with a different genotype was observed, next-generation sequencing of the NS5B PCR product was performed on both samples to rule out mixed infection. Reinfection was defined as a difference in HCV genotype or subtype, or as a significantly different clustering located in different clades in the phylogenetic tree; relapse was defined as significant clustering in the same clade using concatenated NS3-NS5A-NS5B, NS3-NS5A, NS3-NS5B or NS5A-NS5B sequences aligned by neighbour-joining (NJ) and maximum-likelihood (ML) approaches.[12]

Statistical Analysis

The rates of SVR were estimated by an intention-to-treat analysis (ITT), considering all missing data at the date of SVR12 assessment as failures. Discontinuations due to adverse effects and drop-outs were also evaluated. In addition, a modified full analysis set (mFAS) approach was used to calculate the SVR rates excluding patients discontinuing therapy because of non-treatment-related reasons.

Continuous variables were expressed as median (Q1-Q3) and categorical variables as number (%). The chi-square test or Fisher's exact test, when appropriate, were used to compare proportions among treatment groups. The one-way ANOVA test or the Kruskal–Wallis test, whenever necessary, was applied for comparisons of continuous variables among groups. A multivariate logistic regression was carried out to identify factors independently associated with SVR12. Variables associated with SVR12 with a univariate p-value ≤0.2, age categorized by the median and gender were entered into the model. Data were analysed using IBM SPSS 24.0 version (IBM Corporation, Somers, NY, USA) and STATA 9.0 (StataCorp LP, College Station, TX, USA).

Ethics

The study was designed and performed according to the Helsinki declaration and was approved by the local Ethics Committee. All patients gave their written informed consent before being included in the cohorts.

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