Research Paper
Paritaprevir, ritonavir, ombitasvir, and dasabuvir with and without ribavirin in people with HCV genotype 1 and recent injecting drug use or receiving opioid substitution therapy

https://doi.org/10.1016/j.drugpo.2018.10.004Get rights and content

Abstract

Background: Direct-acting antiviral therapy for hepatitis C virus (HCV) infection is safe and effective, but there are little data among people who have recently injected drugs. This study evaluated the efficacy, and safety of paritaprevir/ritonavir, ombitasvir, dasabuvir with or without ribavirin for chronic HCV genotype (G) 1 among people with recent injecting drug use and/or receiving OST.

Methods: D3FEAT is an international open-label study that recruited treatment-naïve participants with recent injecting drug use (previous 6 months) and/or receiving OST with chronic HCV G1 infection between June 2016 and February 2017 in seven countries. Participants received paritaprevir/ritonavir, ombitasvir, dasabuvir with (G1a) or without ribavirin (G1b) administered twice daily in a one-week electronic blister pack (records timing of each dose) for 12 weeks. The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (SVR12).

Results: Among 87 participants (median age 48 years), 23% were female, 8% had cirrhosis, and 90% had G1a. Overall, 71% were receiving OST, 61% injected in the previous six months, 45% injected in the previous month, and 15% injected > daily. Treatment completion was 97% (84 of 87). There were no virological breakthroughs, but three discontinuations (loss to follow-up, n = 1; non-adherence, n = 1; incarceration, n = 1). SVR was 91% (79 of 87, 95% CI, 83%–96%). Five participants who completed treatment did not have SVR (loss to follow-up, n = 1; death, n = 1; virologic relapse, n = 3). Drug use prior to and during treatment did not impact SVR12. Treatment-related adverse events were observed in 46 (53%) patients (six grade 3, no grade 4). Five (6%) patients had at least one serious adverse event (two possibly/probably related to therapy; nausea and myoclonus). Two cases of reinfection were observed.

Conclusion: Paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for 12 weeks is effective among people with HCV genotype 1 with recent injecting drug use and/or receiving OST.

Introduction

Globally, an estimated 71 million people are living with chronic hepatitis C virus (HCV) infection (The Polaris Observatory, 2017), including 6.1 million people who have injected drugs in the previous year (comprising 8.5% of infections globally) (Degenhardt et al., 2017; Grebely, Larney et al., 2018). There also exists an additional, but unquantified burden of HCV among people with former but not recent injecting drug use, including people receiving opioid substitution therapy (OST) for opioid dependence (who may or may not have recently injected drugs) (Larney et al., 2015). Among all new cases of HCV globally, it is estimated that 23% occur among people with recent injecting drug use (WHO, 2017), with a higher proportion of new infections occurring in this group in many countries. As such, expanded HCV therapy among people with recent injecting drug use and those receiving OST will be essential in achieving the WHO targets to eliminate HCV as a major global public health threat.

Post hoc analyses of phase II and III clinical trials of DAA therapy have demonstrated that sustained virologic response (SVR) is similar in those receiving and not receiving OST (Dore et al., 2016a; Feld et al., 2014; Grebely, Dore et al., 2016; Grebely, Jacobson et al., 2017; Grebely, Mauss et al., 2016; Grebely, Puoti et al., 2017; Puoti et al., 2014; Zeuzem et al., 2014). In one of the first trials of DAA therapy among people receiving OST without cirrhosis, participants receiving the regimen of ombitasvir, paritaprevir, ritonavir, dasabuvir, and ribavirin for 12 weeks achieved an SVR12 of 97% (37/38), with no virological failure (Lalezari et al., 2015). However, participants with a positive urine drug screen for non-cannabis drugs at screening were excluded. In the C-EDGE CO-STAR study, among people receiving grazoprevir and elbasvir with no previous treatment experience and HCV genotypes 1, 4 or 6 on stable OST (Dore et al., 2016a), the intention-to-treat (ITT) SVR was 91% (Dore et al., 2016a). However, only 25% had injected drugs within the previous six months (Dore, Grebely et al., 2016). In SIMPLIFY study, among people with recent injecting drug use (previous 6 months) receiving sofosbuvir and velpatasvir with no previous DAA treatment experience and HCV genotypes 1–4, the ITT SVR was 94% (Grebely, Dalgard et al., 2018). Further data on HCV treatment outcomes among people with recent injecting drug use and those receiving OST are needed.

The combination of ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir, and dasabuvir with or without ribavirin is approved for the treatment of patients with HCV genotype 1 infection. In clinical trials, ombitasvir/paritaprevir/ritonavir, and dasabuvir with or without ribavirin demonstrated SVR12 of ≥94% across many patient groups, including those receiving OST (Agarwal et al., 2016; Andreone et al., 2014; Feld et al., 2014, 2016; Ferenci et al., 2014; Fuchs et al., 2016; Lalezari et al., 2015; Poordad et al., 2014; Reau et al., 2015; Sulkowski et al., 2015; Zeuzem et al., 2014).

This study presents the results of an international multicentre, open-label phase IV trial evaluating the efficacy and safety of ombitasvir/paritaprevir/ritonavir, and dasabuvir with or without ribavirin for 12 weeks in people infected with HCV genotype 1 with recent injecting drug use (previous six months) and/or receiving OST.

Section snippets

Patients

From June 2016 to February 2017, participants were enrolled at 19 sites in Australia (n = 4), Canada (n = 6), New Zealand (n = 2), Norway (n = 1), Switzerland (n = 4), and France (n = 2) (D3FEAT, ClinicalTrials.gov: NCT02498015). Study recruitment was performed through a network of drug treatment clinics (n = 3), hospital clinics (n = 13), private practice (n = 1), and community clinics (n = 2) (Grebely, Dalgard et al., 2017). All patients provided written informed consent.

Participants had to

Role of the funding source

The study (including study medications) was funded by a research grant from AbbVie. The funder had no role in the study design, study analysis or interpretation of the study results. JG, EC, and GD had access to the raw data. The sponsor (The Kirby Institute, UNSW Sydney) designed the study, collected the data, managed study samples, monitored study conduct and performed the statistical analysis. JG and GD were responsible for the decision to submit for publication.

Participant characteristics

Of 100 participants screened, 87 were enrolled and received at least one dose of study medication (ITT population, Fig. 1, Table 1). Most participants (90%) had genotype 1a. The median age was 48 years, 23% were female, and 8% had cirrhosis.

At baseline, 61% injected drugs in the previous six months, 45% had injected drugs in the previous month, 15% had injected drugs > daily in the previous month, and 71% were receiving OST (Table 1). The most commonly injected drugs were heroin (30%),

Discussion

In this international multicentre study of people with recent injecting drug use and/or those receiving OST, the SVR12 following treatment with ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin was 91%. Median adherence to this twice-daily therapy was 87%. Injecting drug use prior to or during therapy did not have an impact on SVR12. There was also no change in injecting drug use risk behaviour during treatment. Treatment was well-tolerated. There were three cases of

Acknowledgements

The authors would like to thank the study participants for their contribution to the research, as well as current and past researchers and staff. They would like to acknowledge members of the study group:

Protocol Steering Committee – Jason Grebely (Chair, UNSW Sydney, Sydney, Australia), Gregory Dore (UNSW Sydney, Sydney, Australia), Philippa Marks UNSW Sydney, Sydney, Australia), Olav Dalgard (Akershus University Hospital, Oslo, Norway), Philip Bruggmann (Arud Centres for Addiction Medicine,

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