Approximately one half of all Americans living with Hepatitis C virus (HCV) are drug users, yet they are the least likely to receive HCV treatment. Drug users are presumed non-adherent and therefore denied potentially life-saving therapy. This assumption can only be confirmed or dispelled through prospective pharmacologic and adherence studies in this population. Such studies would be greatly enhanced by an objective, quantitative measure of adherence which does not currently exist in the HCV field. Through the work proposed in this application, sixty HIV/HCV co-infected drug users will be treated with direct acting antiviral agents (DAA) and randomized to receive directly observed DAA therapy (DOT) vs. no directly observed therapy (no-DOT). Patients randomized to no-DOT will have wirelessly observed therapy (WOT) which involves use of a portable medication dispenser that sends a signal to a server with the date and time when the dispenser is opened.
In Aim 1, DAA concentrations will be compared in those randomized to DOT vs. no-DOT. DAA pharmacokinetics will also be defined accounting for clinical factors like degree of hepatic impairment and use of concomitant recreational and antiretroviral drugs. The goal is to quantify adherence in this population and the effect of variable adherence on drug concentrations.
In Aim 2, DAA concentrations (plasma, cellular, hair) will be linked with adherence patterns identified using WOT and DOT. The goal is to identify a drug concentration biomarker that predicts adherence in this population.
In Aim 3, the relationship between DAA adherence (as measured by WOT and DOT and drug concentrations) and rate of cure will be established. The goal is to define the degree of adherence needed for HCV cure. This project is important to human health as it will treat a neglected patient population, use technology to make adherence monitoring convenient, evaluate novel, pharmacokinetic-based adherence measures, determine the contribution of adherence to the likelihood of HCV cure, and generate the first data on DAA forgiveness. The work proposed will generate much needed pharmacology and objective adherence data to encourage the treatment of HCV in drug users.

Public Health Relevance

There is extreme resistance to treating Hepatitis C virus in drug users predicated on the assumption that this population will have poor adherence. The result is an absence of data on the pharmacokinetics and adherence-efficacy relationships for new all-oral Hepatitis C medications in this population. This project will fill these fundamental knowledge gaps and provide much needed data to encourage the treatment of those most affected by this disease.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Khalsa, Jagjitsingh H
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University of Colorado Denver
Schools of Pharmacy
United States
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MacBrayne, Christine E; Marks, Kristen M; Fierer, Daniel S et al. (2018) Effects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate. J Antimicrob Chemother 73:2112-2119
Naggie, Susanna; Marks, Kristen M; Hughes, Michael et al. (2017) Sofosbuvir Plus Ribavirin Without Interferon for Treatment of Acute Hepatitis C Virus Infection in HIV-1-Infected Individuals: SWIFT-C. Clin Infect Dis 64:1035-1042
MacBrayne, Christine E; Kiser, Jennifer J (2016) Pharmacologic Considerations in the Treatment of Hepatitis C Virus in Persons With HIV. Clin Infect Dis 63 Suppl 1:S12-23