Original Research
9 April 2019

Intensive Models of Hepatitis C Care for People Who Inject Drugs Receiving Opioid Agonist Therapy: A Randomized Controlled Trial

Publication: Annals of Internal Medicine
Volume 170, Number 9



Many people who inject drugs (PWID) are denied treatment for hepatitis C virus (HCV) infection, even if they are receiving opioid agonist therapy (OAT). Research suggests that HCV in PWID may be treated effectively, but optimal models of care for promoting adherence and sustained virologic response (SVR) have not been evaluated in the direct-acting antiviral (DAA) era.


To determine whether directly observed therapy (DOT) and group treatment (GT) are more effective than self-administered individual treatment (SIT) in promoting adherence and achieving SVR among PWID receiving OAT.


Three-group, randomized controlled trial conducted from October 2013 to April 2017. (ClinicalTrials.gov: NCT01857245)


Three OAT programs in Bronx, New York.


Persons aged 18 years and older with genotype 1 HCV infection who were willing to receive HCV therapy on site in the OAT program. Of 190 persons screened, 158 were randomly assigned to a study group and 150 initiated treatment: DOT (n = 51), GT (n = 48), and SIT (n = 51).


2 intensive interventions (DOT and GT) and 1 control condition (SIT).


Primary: adherence, measured by using electronic blister packs. Secondary: HCV treatment completion and SVR 12 weeks after treatment completion.


Mean age was 51 years; 65% of participants had positive results on urine drug testing during the 6 months before treatment, and 75% reported ever injecting drugs. Overall adherence, estimated from mixed-effects models using the daily timeframe, was 78% (95% CI, 75% to 81%) and was greater among participants randomly assigned to DOT (86% [CI, 80% to 92%]) than those assigned to SIT (75% [CI, 70% to 81%]; difference, 11% [CI, 5% to 18%]; Bonferroni-corrected P = 0.001). No significant difference in adherence was observed between participants randomly assigned to GT (80% [CI, 74% to 86%]) and those assigned to SIT (difference, 4.7% [CI, −2% to 11%]; Bonferroni-corrected P = 0.29). The HCV treatment completion rate was 97%, with no differences among groups (P = 0.53). Overall SVR was 94% (CI, 89% to 97%); the SVR rate was 98% in the DOT group, 94% in the GT group, and 90% in the SIT group (P = 0.152).


These findings may not be generalizable to PWID not enrolled in OAT programs.


All models of onsite HCV care delivered to PWID in OAT programs resulted in high SVR, despite ongoing drug use. Directly observed therapy was associated with greater adherence than SIT.

Primary Funding Source:

National Institute on Drug Abuse and Gilead Sciences.

Get full access to this article

View all available purchase options and get full access to this article.

Supplemental Material

Supplement. Study Protocol


Degenhardt LPeacock AColledge SLeung JGrebely JVickerman Pet al. Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: a multistage systematic review. Lancet Glob Health. 2017;5:e1192-e1207. [PMID: 29074409]  doi: 10.1016/S2214-109X(17)30375-3
Centers for Disease Control. HCV Surveillance Report 2015. Accessed at http://www.cdc.gov/hepatitis/statistics/2015surveillance/ on 30 January 2018.
Verna ECBrown RS Jr. Hepatitis C virus and liver transplantation. Clin Liver Dis. 2006;10:919-40. [PMID: 17164125]
Ly KNXing JKlevens RMJiles RBWard JWHolmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012;156:271-8. [PMID: 22351712].  doi: 10.7326/0003-4819-156-4-201202210-00004
Lok ASChung RTVargas HEKim AYNaggie SPowderly WG. Benefits of direct-acting antivirals for hepatitis C. Ann Intern Med. 2017;167:812-813. [PMID: 29049502].  doi: 10.7326/M17-1876
Younossi ZMStepanova MHenry LHan KHAhn SHLim YSet al. The effect of interferon-free regimens on health-related quality of life in East Asian patients with chronic hepatitis C. Liver Int. 2018;38:1179-1187. [PMID: 29197140]  doi: 10.1111/liv.13650
Ohashi KIshikawa TSuzuki MAbe HKoyama FNakano Tet al. Health-related quality of life on the clinical course of patients with chronic hepatitis C receiving daclatasvir/asunaprevir therapy: a prospective observational study comparing younger (<70) and elderly (= 70) patients. Exp Ther Med. 2018;15:970-976. [PMID: 29399105]  doi: 10.3892/etm.2017.5488
Younossi ZMStepanova MFeld JZeuzem SSulkowski MFoster GRet al. Sofosbuvir and velpatasvir combination improves patient-reported outcomes for patients with HCV infection, without or with compensated or decompensated cirrhosis. Clin Gastroenterol Hepatol. 2017;15:421-430. [PMID: 27847279]  doi: 10.1016/j.cgh.2016.10.037
El-Kamary SSJhaveri RShardell MD. All-cause, liver-related, and non-liver-related mortality among HCV-infected individuals in the general US population. Clin Infect Dis. 2011;53:150-7. [PMID: 21665867]  doi: 10.1093/cid/cir306
van der Meer AJVeldt BJFeld JJWedemeyer HDufour JFLammert Fet al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584-93. [PMID: 23268517]  doi: 10.1001/jama.2012.144878
Backus LIBelperio PSShahoumian TAMole LA. Direct-acting antiviral sustained virologic response: impact on mortality in patients without advanced liver disease. Hepatology. 2018;68:827-838. [PMID: 29377196]  doi: 10.1002/hep.29811
Mehta SHGenberg BLAstemborski JKavasery RKirk GDVlahov Det al. Limited uptake of hepatitis C treatment among injection drug users. J Community Health. 2008;33:126-33. [PMID: 18165889]  doi: 10.1007/s10900-007-9083-3
Grebely JRaffa JDLai CKrajden MKerr TFischer Bet al. Low uptake of treatment for hepatitis C virus infection in a large community-based study of inner city residents. J Viral Hepat. 2009;16:352-8. [PMID: 19226330]  doi: 10.1111/j.1365-2893.2009.01080.x
Calvo MMacFarlane JZaccaro HCurtis MCabán MFavaro Jet al. Young people who use drugs engaged in harm reduction programs in New York City: overdose and other risks. Drug Alcohol Depend. 2017;178:106-114. [PMID: 28645060]  doi: 10.1016/j.drugalcdep.2017.04.032
Boyd JFast DHobbins MMcNeil RSmall W. Social-structural factors influencing periods of injection cessation among marginalized youth who inject drugs in Vancouver, Canada: an ethno-epidemiological study. Harm Reduct J. 2017;14:31. [PMID: 28583136]  doi: 10.1186/s12954-017-0159-9
Gebo KAKeruly JMoore RD. Association of social stress, illicit drug use, and health beliefs with nonadherence to antiretroviral therapy. J Gen Intern Med. 2003;18:104-11. [PMID: 12542584]
Tucker JSBurnam MASherbourne CDKung FYGifford AL. Substance use and mental health correlates of nonadherence to antiretroviral medications in a sample of patients with human immunodeficiency virus infection. Am J Med. 2003;114:573-80. [PMID: 12753881]
Strathdee SALatka MCampbell JO'Driscoll PTGolub ETKapadia Fet alStudy to Reduce Intravenous Exposures Project. Factors associated with interest in initiating treatment for hepatitis C Virus (HCV) infection among young HCV-infected injection drug users. Clin Infect Dis. 2005;40 Suppl 5:S304-12. [PMID: 15768339]
Stein MDMaksad JClarke J. Hepatitis C disease among injection drug users: knowledge, perceived risk and willingness to receive treatment. Drug Alcohol Depend. 2001;61:211-5. [PMID: 11164684]
Walley AYWhite MCKushel MBSong YSTulsky JP. Knowledge of and interest in hepatitis C treatment at a methadone clinic. J Subst Abuse Treat. 2005;28:181-7. [PMID: 15780548]
Zeremski MDimova RBZavala RKritz SLin MSmith BDet al. Hepatitis C virus-related knowledge and willingness to receive treatment among patients on methadone maintenance. J Addict Med. 2014;8:249-57. [PMID: 24820257]  doi: 10.1097/ADM.0000000000000041
Tsui JIEvans JLLum PJHahn JAPage K. Association of opioid agonist therapy with lower incidence of hepatitis C virus infection in young adult injection drug users. JAMA Intern Med. 2014;174:1974-81. [PMID: 25347412]  doi: 10.1001/jamainternmed.2014.5416
Nolan SDiasLima VFairbairn NKerr TMontaner JGrebely Jet al. The impact of methadone maintenance therapy on hepatitis C incidence among illicit drug users. Addiction. 2014;109:2053-9. [PMID: 25041346]  doi: 10.1111/add.12682
Alderks C. Trends in the use of methadone, buprenorphine, and extended-release naltrexone at substance abuse treatment facilities: 2003-2015 (Update) 2017. Accessed at www.samhsa.gov/data/sites/default/files/report_3192/ShortReport-3192.html on 15 March 2018.
Novick DMKreek MJ. Critical issues in the treatment of hepatitis C virus infection in methadone maintenance patients. Addiction. 2008;103:905-18. [PMID: 18422827]  doi: 10.1111/j.1360-0443.2008.02188.x
Harris KA JrArnsten JHLitwin AH. Successful integration of hepatitis C evaluation and treatment services with methadone maintenance. J Addict Med. 2010;4:20-6. [PMID: 20485532]  doi: 10.1097/ADM.0b013e3181add3de
Litwin AHSoloway IJCockerham-Colas LReynoso SHeo MTenore Cet al. Successful treatment of chronic hepatitis C with triple therapy in an opioid agonist treatment program. Int J Drug Policy. 2015;26:1014-9. [PMID: 26341685]  doi: 10.1016/j.drugpo.2015.08.008
Butner JLGupta NFabian CHenry SShi JMTetrault JM. Onsite treatment of HCV infection with direct acting antivirals within an opioid treatment program. J Subst Abuse Treat. 2017;75:49-53. [PMID: 28237054]  doi: 10.1016/j.jsat.2016.12.014
American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C 2017. Accessed at www.HCVguidelines.org on 15 January 2018.
Akiyama MJAgyemang LArnsten JHHeo MNorton BLSchackman BRet al. Rationale, design, and methodology of a trial evaluating three models of care for HCV treatment among injection drug users on opioid agonist therapy. BMC Infect Dis. 2018;18:74. [PMID: 29426304]  doi: 10.1186/s12879-018-2964-5
Perlis TEDesJarlais DCFriedman SRArasteh KTurner CF. Audio-computerized self-interviewing versus face-to-face interviewing for research data collection at drug abuse treatment programs. Addiction. 2004;99:885-96. [PMID: 15200584]
McLellan ATKushner HMetzger DPeters RSmith IGrissom Get al. The fifth edition of the addiction severity index. J Subst Abuse Treat. 1992;9:199-213. [PMID: 1334156]
Kroenke KSpitzer RLWilliams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-13. [PMID: 11556941]
Stein MRSoloway IJJefferson KSRoose RJArnsten JHLitwin AH. Concurrent group treatment for hepatitis C: implementation and outcomes in a methadone maintenance treatment program. J Subst Abuse Treat. 2012;43:424-32. [PMID: 23036920]  doi: 10.1016/j.jsat.2012.08.007
Sylvestre DLZweben JE. Integrating HCV services for drug users: a model to improve engagement and outcomes. Int J Drug Policy. 2007;18:406-10. [PMID: 17854729]
Information Mediary Corp. Med-ic Smart Label. Accessed at www.informationmediary.com/med-ic on 1 February 2018.
Arnsten JHDemas PAGrant RWGourevitch MNFarzadegan HHoward AAet al. Impact of active drug use on antiretroviral therapy adherence and viral suppression in HIV-infected drug users. J Gen Intern Med. 2002;17:377-81. [PMID: 12047736]
Litwin AH, Li X, Heo M, Hidalgo J, Arnsten JH. Directly observed HCV treatment in methadone clinics—preliminary results [Abstract]. Presented at International Conference on Viral Hepatitis 2011, Baltimore, MD, 11–12 April, 2011. Abstract no. 70762.
Mason KDodd ZGuyton MTookey PLettner BMatelski Jet al. Understanding real-world adherence in the directly acting antiviral era: a prospective evaluation of adherence among people with a history of drug use at a community-based program in Toronto, Canada. Int J Drug Policy. 2017;47:202-208. [PMID: 28619394]  doi: 10.1016/j.drugpo.2017.05.025
Grebely JMauss SBrown ABronowicki JPPuoti MWyles Det al. Efficacy and safety of Ledipasvir/Sofosbuvir with and without ribavirin in patients with chronic HCV genotype 1 infection receiving opioid substitution therapy: analysis of phase 3 ION trials. Clin Infect Dis. 2016;63:1405-1411. [PMID: 27553375]
Dore GJAltice FLitwin AHDalgard OGane EJShibolet Oet alC-EDGE CO-STAR Study Group. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Ann Intern Med. 2016;165:625-634. [PMID: 27537841].  doi: 10.7326/M16-0816
Afdhal NZeuzem SKwo PChojkier MGitlin NPuoti Met alION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-98. [PMID: 24725239]  doi: 10.1056/NEJMoa1402454
Jacobson IMMcHutchison JGDusheiko GDi Bisceglie AMReddy KRBzowej NHet alADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-16. [PMID: 21696307]  doi: 10.1056/NEJMoa1012912
Lawitz EMangia AWyles DRodriguez-Torres MHassanein TGordon SCet al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-87. [PMID: 23607594]  doi: 10.1056/NEJMoa1214853
Osinusi AMeissner EGLee YJBon DHeytens LNelson Aet al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310:804-11. [PMID: 23982366]  doi: 10.1001/jama.2013.109309
Fried MWHadziyannis SJShiffman MLMessinger DZeuzem S. Rapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection. J Hepatol. 2011;55:69-75. [PMID: 21145856]  doi: 10.1016/j.jhep.2010.10.032
Patel MRab SKalapila AGKyle AOkosun ISMiller L. Highly successful hepatitis C virus (HCV) treatment outcomes in human immunodeficiency virus/HCV-coinfected patients at a large, urban, Ryan White clinic. Open Forum Infect Dis. 2017;4:ofx062. [PMID: 28534036]  doi: 10.1093/ofid/ofx062
Zeuzem SFoster GRWang SAsatryan AGane EFeld JJet al. Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med. 2018;378:354-369. [PMID: 29365309]  doi: 10.1056/NEJMoa1702417
Aghemo AColombo M. Response-guided duration of direct acting antiviral therapy for chronic hepatitis C: back to the future? Gastroenterology. 2017;152:1238-1239. [PMID: 28253477]  doi: 10.1053/j.gastro.2017.02.022
Grebely JDalgard OConway BCunningham EBBruggmann PHajarizadeh Bet alSIMPLIFY Study Group. 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;3:153-161. [PMID: 29310928]  doi: 10.1016/S2468-1253(17)30404-1

Information & Authors


Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 170Number 97 May 2019
Pages: 594 - 603


Published online: 9 April 2019
Published in issue: 7 May 2019




Matthew J. Akiyama, MD, MSc
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York (M.J.A., B.L.N., J.H.A., L.A.)
Brianna L. Norton, DO, MPH
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York (M.J.A., B.L.N., J.H.A., L.A.)
Julia H. Arnsten, MD, MPH
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York (M.J.A., B.L.N., J.H.A., L.A.)
Linda Agyemang, MPH
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York (M.J.A., B.L.N., J.H.A., L.A.)
Moonseong Heo, PhD
Clemson University, Clemson, South Carolina (M.H.)
Alain H. Litwin, MD, MS, MPH
University of South Carolina School of Medicine–Greenville and Greenville Health System, Greenville, South Carolina, and Clemson University School of Health Research, Clemson, South Carolina (A.H.L.)
Note: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Disclaimer: The contents of this publication are solely the responsibility of the authors and do not necessarily represent the views of the funding agencies or the U.S. government.
Financial Support: By grants R01DA034086 and K99DA043011 from the National Institute on Drug Abuse. Gilead Sciences also provided support (grant IN-337-1779) for the research and supplied study medication, SOF/LDV.
Disclosures: Dr. Akiyama has served on an advisory board for Gilead Sciences outside the submitted work. Dr. Norton reports grants from Merck and Co. outside the submitted work. Dr. Litwin reports grants from Gilead Sciences during the conduct of the study, and grants and personal fees from Gilead Sciences and Merck Pharmaceuticals outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-1715.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement: Study protocol: See the Supplement. Statistical code: Not available. Data set: Available from Dr. Litwin (e-mail, [email protected]).
Corresponding Author: Alain Litwin, MD, MS, MPH, Department of Medicine, 701 Grove Road, 5th Floor Support Tower, Greenville, SC 29605; e-mail, [email protected] or [email protected].
Current Author Addresses: Drs. Akiyama, Norton, and Arnsten and Ms. Agyemang: 3300 Kossuth Avenue, Bronx, NY 10467.
Dr. Heo: 605 Grove Road, Suite 205, Greenville, SC 29605.
Dr. Litwin: Department of Medicine, 701 Grove Road, 5th Floor Support Tower, Greenville, SC 29605.
Author Contributions: Conception and design: J.H. Arnsten, A.H. Litwin.
Analysis and interpretation of the data: M.J. Akiyama, J.H. Arnsten, M. Heo, A.H. Litwin.
Drafting of the article: M.J. Akiyama, B.L. Norton, J.H. Arnsten, L. Agyemang, A.H. Litwin.
Critical revision for important intellectual content: M.J. Akiyama, B.L. Norton, J.H. Arnsten, M. Heo, A.H. Litwin.
Final approval of the article: M.J. Akiyama, B.L. Norton, J.H. Arnsten, L. Agyemang, M. Heo, A.H. Litwin.
Provision of study materials or patients: A.H. Litwin.
Statistical expertise: M. Heo.
Obtaining of funding: M. Heo, A.H. Litwin.
Administrative, technical, or logistic support: J.H. Arnsten, L. Agyemang, A.H. Litwin.
Collection and assembly of data: M.J. Akiyama, L. Agyemang, M. Heo, A.H. Litwin.
This article was published at Annals.org on 9 April 2019.

Metrics & Citations



If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.


Download article citation data for:
Matthew J. Akiyama, Brianna L. Norton, Julia H. Arnsten, et al. Intensive Models of Hepatitis C Care for People Who Inject Drugs Receiving Opioid Agonist Therapy: A Randomized Controlled Trial. Ann Intern Med.2019;170:594-603. [Epub 9 April 2019]. doi:10.7326/M18-1715

View More

Get Access

Login Options:

You will be redirected to acponline.org to sign-in to Annals to complete your purchase.

Access to EPUBs and PDFs for FREE Annals content requires users to be registered and logged in. A subscription is not required. You can create a free account below or from the following link. You will be redirected to acponline.org to create an account that will provide access to Annals. If you are accessing the Free Annals content via your institution's access, registration is not required.

Create your Free Account

You will be redirected to acponline.org to create an account that will provide access to Annals.

View options


View PDF/ePub

Related in ACP Journals

Full Text

View Full Text







Copy the content Link

Share on social media