Research ArticleResponse to direct-acting antiviral therapy among ongoing drug users and people receiving opioid substitution therapy
Graphical abstract
Introduction
The epidemic of hepatitis C virus (HCV) infection has been driven in many countries by parenteral transmission through shared needles among people who inject drugs (PWID).[1], [2] Some reports have found that many PWID have a high willingness to receive HCV treatment.[3], [4] However, treatment uptake in the interferon era among PWID was very low, with about 1–2% of all HCV-infected PWID treated yearly.[5], [6] Most probably, this low incorporation of PWID to HCV treatment was due to barriers at different levels, including the poor tolerability of interferon. Simple, highly effective and safer all-oral direct-acting antivirals (DAAs) should have increased the uptake of HCV treatment among PWID. Indeed, current guidelines support the need to scale up treatment in PWID to effectively impact the HCV epidemic.[7], [8] However, patients with ongoing drug use or on opioid agonist therapy (OAT) are ineligible in some settings9 or might not be considered suitable to receive DAAs by some practitioners.10 To further complicate the scenario, PWID with HCV infection have been underrepresented in most clinical trials with DAAs.[11], [12], [13], [14] Indeed, only a few trials have specifically assessed treatment with all-oral DAA regimens in individuals on OAT.[15], [16], [17], [18]
In real-world conditions, the efficacy of DAAs may be lower, there may be more frequent severe adverse events, and there may be a higher rate of loss to follow-up and reinfection than in clinical trials. In a large study of people receiving stable OAT and DAA therapy, approximately two-thirds of PWID on stable OAT used illicit drugs before and during treatment with DAA combinations.[16], [18] Due to concerns regarding the impact of ongoing drug use on adherence, response to therapy, and potential for reinfection, there are some clinicians who may not offer DAA therapy to people with ongoing drug use.19 Moreover, the DAA efficacy reported in patients on OAT, based on trials with specific programs to supervise and enhance adherence, may not be generalizable to other people using drugs in the real-world setting.[15], [16], [17] Supervision of adherence within some clinical trials using electronic devices[17], [18] or dedicated health care professionals to follow patients day by day[16], [17] is ideal but not available nor reimbursed in most settings. Therefore, real-world studies assessing the efficacy of currently used HCV therapy in PWID on OAT are required. In the present study, we compared the rates of sustained virologic response (SVR) to interferon-free DAA combinations among individuals receiving or not receiving OAT in routine clinical practice.
Section snippets
Design and patients
This was a prospective multicohort study of HCV-infected patients who started DAA combinations in 33 Infectious Diseases Units in Spain and who were recruited at the HEPAVIR-DAA cohort (NCT02057003) or at the GEHEP-MONO cohort (NCT02333292). The HEPAVIR-DAA cohort, which includes HIV/HCV-coinfected patients, and the GEHEP-MONO cohort, which recruits HCV-monoinfected individuals, are ongoing prospective multicenter cohorts of patients receiving DAA combinations prescribed in clinical practice.
Baseline characteristics of the study population
Overall, 1,752 patients included in the cohorts started interferon-free DAA combinations between June 2013 and March 2017. Out of them, 818 (47%) participants reported no history of injecting drug use, 735 (42%) had a history of injecting drug use and were not receiving OAT and 199 (11%) had a history of injecting drug use and were receiving OAT (including methadone, n = 192; buprenorphine, n = 4; buprenorphine/naloxone, n = 3). Among PWID, 11% (103 of 934) reported recent drug use (47 of 199
Discussion
HCV-infected PWID, particularly active drug users, have a lower SVR12 rate to DAA combinations in clinical practice. This fact is mainly attributable to higher rates of discontinuations due to adverse events and, especially, loss to follow-up, and not to virologic failure. A number of key factors related with a lower likelihood of SVR are more frequently observed in PWIDs, but accounting for ongoing drug use during DAA therapy nearly closed the gap in SVR rates between the study groups.
One of
Financial support
This study was partly supported by grants from the Ministerio de Economía, Industria y competitividad, Instituto de Salud Carlos III (grants no: PI15/01607; PI15/00713, PI16/01443) and from Grupo de Estudio de Hepatitis Vírica-SEIMC (grants no: GEHEP-001 & GEHEP-004). J.M. is the recipient of a grant from the Servicio Andaluz de Salud de la Junta de Andalucía (grant number B-0037). J.A.P. is recipient of an intensification grant from the Instituto de Salud Carlos III (grant number Programa-I3SNS
Conflict of interest
JM has been an investigator in clinical trials supported by Bristol-Myers Squibb, Gilead and Merck Sharp & Dome. He has received lectures fees from Gilead, Bristol-Myers Squibb, and Merck Sharp & Dome, and consulting fees from Bristol-Myers-Squibb, Gilead, and Merck Sharp & Dome. JAP reports having received consulting fees from Bristol-Myers Squibb, Abbvie, Gilead, Merck Sharp & Dome, and Janssen Cilag. He has received research support from Bristol-Myers Squibb, Abbvie and Gilead and has
Authors’ contributions
Juan Macías: Study design, data collection, data analysis, data interpretation, writing and reviewing the paper. Luis E. Morano: Data collection, data analysis, data interpretation, reviewing the paper. Francisco Téllez: Data collection, data analysis, data interpretation, reviewing the paper. Rafael Granados: Data collection, data analysis, data interpretation, reviewing the paper. Antonio Rivero-Juárez: Data collection, data analysis, data interpretation, reviewing the paper. Rosario
References (34)
- et al.
Can hepatitis C virus infection be eradicated in people who inject drugs?
Antiviral Res
(2014) - et al.
Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine
J Hepatol
(2015) - et al.
Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial
Lancet Gastroenterol Hepatol
(2018) - et al.
Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study
Lancet Infect Dis
(2017) - et al.
Ledipasvir-sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial
Lancet Gastroenterol Hepatol
(2017) - et al.
Epidemiology and natural history of HCV infection
Nat Rev Gastroenterol Hepatol
(2013) - et al.
Factors associated with interest in initiating treatment for hepatitis C Virus (HCV) infection among young HCV-infected injection drug users
Clin Infect Dis
(2005) - et al.
Assessment and treatment of hepatitis C virus infection among people who inject drugs in the opioid substitution setting: ETHOS study
Clin Infect Dis
(2013) - et al.
Uptake of hepatitis C treatment among people who inject drugs attending Needle and Syringe Programs in Australia, 1999–2011
J Viral Hepat
(2014) - et al.
Continued low uptake of treatment for hepatitis C virus infection in a large community-based cohort of inner city residents
Liver Int
(2014)