Ombitasvir/Paritaprevir/r and Dasabuvir Plus Ribavirin in HCV Genotype 1-Infected Patients on Methadone or Buprenorphine

Journal of Hepatology

Articles in Press

Jacob Lalezari, J. Greg Sullivan, Peter Varunok, Edward Galen, Kris V. Kowdley, Vinod Rustgi, Humberto Aguilar, Franco Felizarta, Barbara McGovern, Martin King, Akshanth R. Polepally, Daniel E. Cohen

DOI: http://dx.doi.org/10.1016/j.jhep.2015.03.029
Open access funded by the Author(s)
Publication stage: In Press Accepted Manuscript

Publication History

Published Online: March 31, 2015
Accepted: March 25, 2015
Received in revised form: March 17, 2015
Received: September 19, 2014

Abstract

Background & Aims

HCV-infected patients with a history of injection drug use have low rates of initiation and completion of interferon-based therapies. This study evaluated efficacy, safety, and pharmacokinetics of a 12-week all-oral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir +ribavirin in HCV genotype 1-infected patients on stable opioid replacement therapy.

Methods

This was a phase 2, multicenter, open-label, single arm study in treatment-naïve or peginterferon/ribavirin-treatment experienced HCV genotype 1-infected patients on methadone or buprenorphine +/-naloxone. Patients received 12 weeks of co-formulated ombitasvir/paritaprevir/ritonavir(25mg/150mg/100mg once daily) and dasabuvir(250mg twice daily) +weight-based ribavirin. The primary efficacy endpoint was sustained virologic response 12 weeks post-treatment.

Results

Thirty-eight non-cirrhotic patients on chronic methadone(n=19) or buprenorphine(n=19) were enrolled. A total of 37 patients(97.4%) had a sustained virologic response 12 weeks post-treatment. No patient had a viral breakthrough or relapse. One patient discontinued due to serious adverse events unrelated to study drug (cerebrovascular accident and sarcoma). The most frequent adverse events were nausea, fatigue, and headache. Eight patients had on-treatment hemoglobin concentrations <10g/dL. Pharmacokinetic analyses indicated no clinically meaningful impact of methadone or buprenorphine on ombitasvir, paritaprevir, ritonavir, dasabuvir, or dasabuvir M1 metabolite exposures. No dose adjustments of methadone or buprenorphine were required

Conclusions

The interferon-free regimen of ombitasvir/paritaprevir/r and dasabuvir +ribavirin for 12 weeks was well-tolerated and achieved sustained virologic response in 97.4% of patients on opioid substitution therapy in this study. This all-oral regimen may provide an effective alternative to interferon-based therapies for HCV-infected patients with a history of injection drug use.

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Barriers and facilitators for assessment and treatment of hepatitis C virus infection in the opioid substitution treatment setting: insights from the ETHOS study

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

Original Article

C. Treloar^1,*, J. Rance¹, G. J. Dore², J. Grebely² the ETHOS Study Group

Article first published online: 3 DEC 2013

DOI: 10.1111/jvh.12183

© 2013 John Wiley & Sons Ltd

Abstract

Keywords: hepatitis C;  opiate substitution treatment;  qualitative research;  treatment

Summary

Provision of hepatitis C virus (HCV) assessment and treatment via opioid substitution treatment (OST) clinics has been posed as an effective means of engaging populations with high HCV prevalence. This study explores OST client and health professional reports concerning barriers and facilitators affecting the delivery and uptake of HCV care and treatment within OST settings. In-depth interviews were conducted with 57 clients, 16 staff from four NSW clinics participating in the Australian ETHOS study and three peer workers. Client participants included those who had not had HCV assessment; those who had HCV assessment only; and those who were awaiting or undertaking HCV treatment. A clear difference in decisions about HCV treatment emerged between participant groups. For those who have not been assessed, barriers to engaging with HCV care included the perception that they were physically well, were not experiencing HCV symptoms, had other life priorities and were concerned about the side effects and tolerability of treatment. Those who had engaged with care expressed motivations stemming from seeing friends becoming unwell, wanting to live longer and hearing positive stories of treatment. For those interested in HCV treatment, issues related to both provider and setting were important, such as presence of an engaged clinician, an accessible treatment pathway and availability of support. In this integrated care model, some barriers to HCV care and treatment (particularly those relating to health provider and the system) are minimized. In this setting, HCV treatment remained an unattractive option for a significant number of clients. Providing ways for those without HCV symptoms to be assessed for liver damage may be important to open up alternative conversations about HCV care. Further, the importance of a changing discourse of treatment is apparent from these data and could be enhanced by peer communication that provides information about successful treatment experiences.

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Methadone Linked to Prolonged QTc Interval

September 5, 2013

Keith Henry, MD reviewing Vallecillo G et al. Clin Infect Dis 2013 Aug 14. Keith Henry, MD

A prolonged QTc interval in HIV-infected patients on methadone was associated with higher methadone doses, hepatitis C liver disease, and ART-naive status. Keith Henry, MD

Illicit opioid use is associated with increased risk for HIV infection. Methadone is an effective drug for the long-term management of opioid-dependent HIV-infected patients, although safety concerns have been identified (i.e., cardiac arrhythmias such as prolonged QTc interval and torsades de pointes).

In a cross-sectional study, HIV-infected patients on methadone maintenance therapy followed at a single outpatient clinic in Spain underwent 12-lead electrocardiography 24 hours after supervised methadone administration. Individuals with known cardiac disease, drug-positive urine tests, electrolyte abnormalities, or changes in antiretroviral therapy (ART) regimen or methadone dose in the preceding 2 months were excluded.

Of the 91 study participants (64% men; 100% white; median age, 44.5), 68 (75%) were on ART; the regimen for 56 of them included a boosted protease inhibitor. The median nadir and current CD4 counts were 232 and 438 cells/mm3, respectively. The median methadone dose was 70 mg/day, and the mean QTc interval was 438 milliseconds. A prolonged QTc interval (>450 ms) was documented in 33 participants (36%), including 3 with intervals >500 milliseconds. On multiple linear regression analysis, higher methadone dose, chronic hepatitis C–induced cirrhosis, and ART-naive state were associated with a prolonged QTc interval.

Comment

In a cross-sectional study without a control population, it is difficult to fully assess the clinical risk posed by the reported QTc abnormalities.

A prolonged QTc interval was associated with being antiretroviral-naive, but was not observed with use of protease inhibitors (which have been linked in other studies to QTc prolongation). Complicating the situation was the common use of other QTc-prolonging drugs (58% of the participants were taking antipsychotics, antidepressants, antiepileptics, or antibiotics). The study findings remind clinicians of the possible effects of drugs on cardiac conduction and the need to be diligent in monitoring for potential problems (often including input from an HIV-savvy pharmacist, as well as baseline and follow-up electrocardiograms).

Citation(s):

Vallecillo G et al. Risk of QTc prolongation in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy. Clin Infect Dis 2013 Aug 14; [e-pub ahead of print]. (http://dx.doi.org/10.1093/cid/cit467)

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Prevention and Management of Hepatitis C Virus Infection Among People Who Inject Drugs: Moving the Agenda Forward

Provided by NATAP

All PDFs attached

Clinical Infectious Diseases
Volume 57 suppl 2 August 15, 2013

- Moving the Agenda Forward: The Prevention and Management of Hepatitis C Virus Infection Among People Who Inject Drugs
Jason Grebely, Philip Bruggmann, Markus Backmund, and Gregory J. Dore
Moving the Agenda Forward: The Prevention and Management of Hepatitis C Virus Infection Among People Who Inject Drugs

- Injection Drug Use and Hepatitis C Virus Infection in Young Adult Injectors: Using Evidence to Inform Comprehensive Prevention
Kimberly Page, Meghan D. Morris, Judith A. Hahn, Lisa Maher, and Maria Prins
Injection Drug Use and Hepatitis C Virus Infection in Young Adult Injectors: Using Evidence to Inform Comprehensive Prevention

- Combination Interventions to Prevent HCV Transmission Among People Who Inject Drugs: Modeling the Impact of Antiviral Treatment, Needle and Syringe Programs, and Opiate Substitution Therapy
Natasha K. Martin, Matthew Hickman, Sharon J. Hutchinson, David J. Goldberg, and Peter Vickerman
Combination Interventions to Prevent HCV Transmission Among People Who Inject Drugs: Modeling the Impact of Antiviral Treatment, Needle and Syringe Programs, and Opiate Substitution Therapy

- Hepatitis C Virus Vaccines Among People Who Inject Drugs
Andrea L. Cox and David L. Thomas
Hepatitis C Virus Vaccines Among People Who Inject Drugs

- Understanding Barriers to Hepatitis C Virus Care and Stigmatization From a Social Perspective
Carla Treloar, Jake Rance, and Markus Backmund
Understanding Barriers to Hepatitis C Virus Care and Stigmatization From a Social Perspective

- Models of Care for the Management of Hepatitis C Virus Among People Who Inject Drugs: One Size Does Not Fit All
Philip Bruggmann and Alain H. Litwin
Models of Care for the Management of Hepatitis C Virus Among People Who Inject Drugs: One Size Does Not Fit All

- Assessment and Treatment of Hepatitis C Virus Infection Among People Who Inject Drugs in the Opioid Substitution Setting: ETHOS Study
Maryam Alavi, Jason Grebely, Michelle Micallef,, Adrian J. Dunlop,, Annie C. Balcomb, Carolyn A. Day, Carla Treloar, Nicky Bath, Paul S. Haber, Gregory J. Dore, and on behalf of the Enhancing Treatment for Hepatitis C in Opioid Substitution Settings (ETHOS) Study Group
Assessment and Treatment of Hepatitis C Virus Infection Among People Who Inject Drugs in the Opioid Substitution Setting: ETHOS Study

- Enhancing Assessment and Treatment of Hepatitis C in the Custodial Setting Jeffrey J. Post, Amber Arain, and Andrew R. Lloyd
Enhancing Assessment and Treatment of Hepatitis C in the Custodial Setting

- Peer Support Models for People With a History of Injecting Drug Use Undertaking Assessment and Treatment for Hepatitis C Virus Infection
Sione Crawford and Nicky Bath
Peer Support Models for People With a History of Injecting Drug Use Undertaking Assessment and Treatment for Hepatitis C Virus Infection

- Treatment of Hepatitis C Virus Infection Among People Who Are Actively Injecting Drugs: A Systematic Review and Meta-analysis
Esther J. Aspinall, Stephen Corson, Joseph S. Doyle, Jason Grebely, Sharon J. Hutchinson, Gregory J. Dore, David J. Goldberg, and Margaret E. Hellard
Treatment of Hepatitis C Virus Infection Among People Who Are Actively Injecting Drugs: A Systematic Review and Meta-analysis

- Directly Observed Pegylated Interferon Plus Self-Administered Ribavirin for the Treatment of Hepatitis C Virus Infection in People Actively Using Drugs: A Randomized Controlled Trial
Robert J. Hilsden, Gisela Macphail, Jason Grebely, Brian Conway, and Samuel S. Lee
Directly Observed Pegylated Interferon Plus Self- Administered Ribavirin for the Treatment of Hepatitis C Virus Infection in People Actively Using Drugs: A Randomized Controlled Trial

- Psychoeducation Improves Hepatitis C Virus Treatment During Opioid Substitution Therapy: A Controlled, Prospective Multicenter Trial
Jens Reimer, Christiane Sybille Schmidt, Bernd Schulte, Dirk Gansefort, Jorg Golz, Guido Gerken, Norbert Scherbaum, Uwe Verthein, and Markus Backmund
Psychoeducation Improves Hepatitis C Virus Treatment During Opioid Substitution Therapy: A Controlled, Prospective Multicenter Trial

- Hepatitis C Virus Reinfection Following Treatment Among People Who Use Drugs
Bart P. Grady, Janke Schinkel, Xiomara V. Thomas, and Olav Dalgard
Hepatitis C Virus Reinfection Following Treatment Among People Who Use Drugs

- Management of Mental Health Problems Prior to and During Treatment of Hepatitis C Virus Infection in Patients With Drug Addiction
Martin Schaefer, Rahul Sarkar, and Crisanto Diez-Quevedo
Management of Mental Health Problems Prior to and During Treatment of Hepatitis C Virus Infection in Patients With Drug Addiction

- Drug-Drug Interactions in the Treatment of HCV Among People Who Inject Drugs Stefan Mauss and Hartwig Klinker
Drug-Drug Interactions in the Treatment of HCVAmong People Who Inject Drugs

- Recommendations for the Management of Hepatitis C Virus Infection Among People Who Inject Drugs
Recommendations for the Management of Hepatitis C Virus Infection Among People Who Inject Drugs

Geert Robaeys, Jason Grebely, Stefan Mauss, Philip Bruggmann, Joseph Moussalli, Andrea De Gottardi, Tracy Swan, Amber Arain, Achim Kautz, Heino Stover, Heiner Wedemeyer, Martin Schaefer, Lynn Taylor, Markus Backmund, Olav Dalgard, Maria Prins, Gregory J. Dore, and on behalf of the International Network on Hepatitis in Substance Users

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Combining treatments for people who inject drugs is the first step towards eliminating hepatitis C

Public release date: 24-Jul-2013
Contact: Caroline Clancy
caroline.clancy@bristol.ac.uk
44-011-792-88086
University of Bristol

The burden of liver disease could be dramatically reduced by scaling up the combination of interventions for hepatitis C infection among people who inject drugs according to University of Bristol researchers. The findings, published today [24 July], form part of new global recommendations on treating the virus.

Around 150 million people globally are chronically infected with the hepatitis C virus (HCV)1 – a major cause of liver disease that can lead to serious complications such as liver failure or cancer, which are associated with considerable costs to the health care system. In developed countries the majority of transmissions and cases are among people who inject drugs2 – in the UK, this equates to around 90 per cent of hepatitis C infections.3

The study, published today in the journal Clinical Infectious Diseases by Dr Natasha Martin and colleagues at University of Bristol, the London School of Hygiene and Tropical Medicine and Health Protection Scotland, suggests that combining HCV antiviral treatment with opiate substitution therapy (OST) such as methadone and buprenorphine, and high-coverage needle and syringe programmes (HCNSP) is critical for achieving substantial reductions by up to 50 per cent over ten years.

Matthew Hickman, Professor in Public Health and Epidemiology at Bristol's School of Social and Community Medicine and co-author of the research, said: "High-coverage needle and syringe programmes (NSP) and opiate substitution therapy (OST) are the key primary interventions to treat hepatitis C among people who inject drugs; but HCV treatment is required if we want to achieve greater than 45 per cent reduction in HCV prevalence over a ten year period.

"Our model projections show that scaling up OST and high coverage NSP can reduce the number of HCV treatments required to achieve reductions in HCV – and emphasises the importance of a combination of interventions. Further research is needed to examine the cost effectiveness and affordability of scaling up HCV treatment."

The research supports the first set of global recommendations, published by the International Network on Hepatitis Care in Substance Users (INHSU), ever released for treating hepatitis C in people who inject drugs which has shown that treatment can be very successful when barriers are addressed within a supportive environment.

Philip Bruggmann, President of the INHSU, who have published the recommendations on treating the disease in substance users, said: "Reducing the significant burden of liver disease related to hepatitis C internationally will require improved HCV care in the population most affected: those people who currently inject or formerly injected drugs. By providing appropriate care to this group, we can reduce the burden of hepatitis C-related liver disease in this vulnerable population and slow the spread of this global epidemic. These new recommendations serve as a first step in eliminating hepatitis C."

###

Paper

The study 'Combination Interventions to Prevent HCV Transmission Among People Who Inject Drugs: Modeling the Impact of Antiviral Treatment,Needle and Syringe Programs, and Opiate Substitution Therapy' is published today [24 July] in the journal Clinical Infectious Diseases.

Global recommendations

The global recommendations are published online today [24 July] in the journal Clinical Infectious Diseases in a supplement entitled 'Prevention and Management of Hepatitis C Virus Infection Among People Who Inject Drugs: Moving the Agenda Forward'.

Further information:

1. World Health Organisation: http://www.who.int/mediacentre/factsheets/fs164/en/

2. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5:558-67

3. An evidence synthesis approach to estimating hepatitis C prevalence in England and Wales. Stat Methods Med Res 2009; 18:361-79.

4. About hepatitis C

Hepatitis C is a blood-borne virus that predominantly infects the cells of the liver. This can result in inflammation and significant damage to the liver. It can also affect the liver's ability to perform its essential functions. Although it has always been regarded as a liver disease - 'hepatitis' means 'inflammation of the liver' - recent research has shown that the hepatitis C virus (HCV) affects a number of other areas of the body. These can include the digestive system, the lymphatic system, the immune system and the brain.

Source: The Hepatitis Trust - http://www.hepctrust.org.uk/Hepatitis_C_Info/About+Hepatitis+C/About+Hepatitis+C

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