Research Article
Response to direct-acting antiviral therapy among ongoing drug users and people receiving opioid substitution therapy

https://doi.org/10.1016/j.jhep.2019.02.018Get rights and content

Highlights

  • HCV-infected PWID achieve high SVR12 rates with IFN-free antiviral regimens in clinical practice.

  • PWID have lower SVR12 rates than patients who never used drugs.

  • Active drug use during antiviral treatment was an independent predictor of lower response, opioid agonist therapy was not.

  • The main reasons for non-response among PWID are discontinuations due to adverse events and, particularly, drop-outs.

Background & Aims

People who inject drugs (PWID) and are on opioid agonist therapy (OAT) might have lower adherence to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) and, therefore, lower rates of sustained virologic response (SVR). Because of this, we compared the SVR rates to interferon-free DAA combinations in individuals receiving OAT and those not receiving OAT in a real-world setting.

Methods

The HEPAVIR-DAA cohort, recruiting HIV/HCV-coinfected patients (NCT02057003), and the GEHEP-MONO cohort (NCT02333292), including HCV-monoinfected individuals, are ongoing prospective multicenter cohorts of patients receiving DAAs in clinical practice. We compared SVR 12 weeks after treatment (SVR12) in non-drug users and PWID, including those receiving or not receiving OAT. Intention-to-treat and per protocol analyses were performed.

Results

Overall, 1,752 patients started interferon-free DAA treatment. By intention-to-treat analysis, 778 (95%, 95% CI 93%–96%) never injectors, 673 (92%, 95% CI 89%–93%) PWID not on OAT and 177 (89%, 95% CI 83%–92%) PWID on OAT achieved SVR12 (p = 0.002). SVR12 rates for ongoing drug users (with or without OAT) were 68 (79%) compared with 1,548 (95%) for non-drug users (p <0.001). Among ongoing drug users, 15 (17%) were lost-to-follow-up, and 3 (3.5%) became reinfected. In the per protocol analysis, 97% never injectors, 95% PWID not on OAT and 95% PWID on OAT achieved SVR12 (p = 0.246). After adjustment, ongoing drug use was associated with SVR12 (intention-to-treat) and OAT use was not.

Conclusions

HCV-infected PWID achieve high SVR12 rates with DAAs whether they are on OAT or not, but their response rates are lower than those of patients who never used drugs. This is mainly attributable to more frequent loss to follow-up. Accounting for active drug use during DAA therapy nearly closed the gap in SVR rates between the study groups.

Lay summary

Patients with hepatitis C virus infection who are on opioid agonist therapy can achieve high cure rates with current treatments. The use of illicit drugs during treatment can drive drop-outs and reduce cure rates. However, hepatitis C can be cured in most of those using drugs who complete treatment and follow-up.

Clinical trial number: HEPAVIR-DAA cohort, NCT02057003; GEHEP-MONO cohort, NCT02333292.

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

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