A Direct obserVed therApy vs fortNightly CollEction Study for HCV Treatment - ADVANCE HCV Study
Condition: Hepatitis C
MeSH terms: Hepatitis C
Study type: Interventional
Phase: Phase 2

Summary: 
      Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000
      Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV
      infection is intravenous drug use. As HCV is highly infectious by the blood borne route
      through needle sharing, it can infect the person who injects drugs (PWID) early in their
      habit.

      Around two thirds of people who are infected are unaware of it, and often show no symptoms
      over a long period of time. While there is presently no vaccination for Hepatitis C, improved
      treatments with shorter duration are now available. This raises the possibility of using
      therapy as prevention, turning the epidemic off at source, by targeting active PWID who are
      the main source of new infections. Modelling work illustrates the startling possibility and
      impact of treating drug users to reduce the prevalence of HCV.

      The focus of this trial will be to ascertain whether oral treatment regimens are effective in
      the treatment as prevention scenario in an active PWID population where illicit drug taking
      and poor adherence may reduce treatment efficacy. The investigators will trial 3 different
      methods of delivering treatment and will trial an unlicensed combined treatment against HCV
      genotype 3 infection of shortened duration since current regimens for this genotype are
      limited.

      The investigators will recruit 135 participants and randomise them to one of three arms:
      daily, directly observed therapy; fortnightly dispensing of drugs; fortnightly dispensing of
      drugs with a psychological adherence intervention. Randomisation will be stratified according
      to HCV genotype. Participants will be treated for 12 or 8 weeks depending on genotype and
      followed up 12 weeks post treatment for the measurement of sustained viral response (SVR).
      The primary outcome measure will be SVR at 12 weeks post treatment (SVR12), as this measure
      of cure is the determinant of sufficient compliance and efficacy within the 3 treatment arms.
      Analysis will be by modified intention to treat of all participants who receive one dose of
      therapy, to show non-inferiority fortnightly dispensing is easier to deliver than daily
      dispensing.
    

Detailed description: 
      Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000
      Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV
      infection is intravenous drug use. As HCV is highly infectious by the blood borne route
      through needle sharing, it can infect the PWID early in their habit. With the advent of more
      effective therapies of shortening duration, it raises the possibility of using therapy as
      prevention, turning the epidemic off at source, by targeting active infected drug users who
      are the main source of new infections.

      The modelling work of Martin et al, raises the startling possibility of the profound impact
      of treating small numbers of drug users on the prevalence of HCV, the work shows that
      treating as few as 10-20 per 1000 drug users per year can reduce HCV prevalence by 50-90%
      over 10 years. This has generated in the HCV field, the concept of treatment as prevention.
      The scale of the benefit is exponentially related to prevalence of HCV in the population, the
      lower the prevalence the bigger the impact. The model has some limitations, it groups all
      drug users together and assumes a similar risk of infection for those on methadone and those
      actively injecting and assumes a high rate of turn over from methadone back to active
      injecting and further assumes treatment is only possible during the opiate substitution
      phase.

      Oral anti-HCV regimens that are interferon free and have virtually no side-effects are now
      the standard of care in conventional treatment populations. The medication should be taken
      daily to optimise therapeutic success, and if adherence is poor in the actively injecting
      population it is possible that the effectiveness of the new oral drugs will be reduced. It is
      key to know if all oral directly acting antivirals (DAA) regimens are robust and maintain SVR
      rates in this population. The real world SVR rate combined with drug cost, re-infection rate
      and emergence of viral resistance will determine if this treatment as prevention model is
      cost-effective with DAAs. Directly observed therapy (DOT) is the ultimate adherence aid, but
      it is more costly and draconian so that it may discourage participants, especially this
      group, from taking up therapy. Therefore the investigators need to demonstrate that treatment
      uptake and adherence is sufficient to maintain the SVR rate at a level which makes treatment
      as prevention cost effective. Three means of delivery will be compared: daily DOT vs
      fortnightly pick up of therapy vs. fortnightly pick-up of therapy with a psychological
      intervention for adherence. The DOT method of treatment has not been explored in this
      difficult to find and engage population previously. Contingency management in the form of
      protein drinks for successful completion of each fortnight of treatment will be provided in
      all three arms of the trial. A comparison of the three pathways mentioned above will show
      which pathway shows best acceptability to participants and greatest compliance

      The advent of DAAs with their reduced side effect profiles, shorter treatment duration and
      high SVR rates have the potential to reduce the burden of treatment providing high levels of
      adherence can be maintained. However, the use of DAAs alone are unlikely to be sufficient to
      achieve the required levels of adherence. In addition, the use of DAAs will not address the
      psychosocial factors known to influence adherence. This trial will therefore investigate the
      effectiveness of a nurse-led educational intervention for adherence to DAAs in a PWID
      population.

      Whilst the combination of Grazoprevir and Elbasvir is licensed for treatment of HCV genotype
      1, treatment of HCV genotype 3 is more problematic. The C-SWIFT trial has recently shown that
      the combination of Grazoprevir, Elbasvir and Sofosbuvir is an effective and safe 8 week
      treatment for HCV genotype 3, resulting in high SVR rates. Whilst all 3 drugs are licensed
      for treatment of HCV, the combination is not yet licensed. This combination will be used to
      treat HCV genotype 3 infections in this trial.

      Hepatitis C virus is prone to develop resistance to DAAs since it has a high replication rate
      and therefore forms large numbers of genetically-distinct viral variants. The investigators
      will investigate whether participants who do not achieve SVR are infected with a drug
      resistant strain of HCV by sequencing the NS3 and NS5A regions of viral nonstructural (NS)
      protein present within their blood. The proteins of these genes are targeted by the DAA
      medications and if their structure is altered the DAA may no longer be effective.

      The trial will also explore whether the taking of illicit drugs affects the efficacy of
      treatment. While the main effect is likely to be via adherence, it is also possible that some
      of the illicit drugs may interact with the DAAs. A log of illicit drugs used by the
      participants will be kept and used to identify any candidate interactions for further
      investigation.

      This is a randomised, un-blinded trial which will be conducted in the needle exchange
      services and pharmacies across Tayside, designed to evaluate the efficacy and feasibility of
      DAA therapy, in HCV positive, genotype 1 and 3, active PWIDs, administered via three
      different routes:

        1. DOT,

        2. Fortnightly pick-up

        3. Fortnightly pick-up with psychological intervention.

      Participants included in the trial will have a reactive Dry Blood Spot (DBS) test to confirm
      HCV infection, polymerase chain reaction (PCR) test to confirm active infection and will
      currently be using illicit drugs, as confirmed by the participant. Drug screening (by urine
      sample) will not be tested at that time.

      Participants will be stratified by the genotype of their HCV infection; genotype 1 vs
      genotype 3 and randomised to one of three groups; DOT, fortnightly pick-up, or fortnightly
      pick-up with psychological adherence intervention.

      All PWID are encouraged to have a DBS test annually as part of clinical practice in Tayside.
      Upon receipt of a reactive DBS test, potential participants will be briefed about the trial
      by the specialist nurse or other trained member of staff and given a participant information
      sheet (PIS) informing them of what is involved. Willing individuals will provide written
      informed consent and will then have safety bloods drawn to determine eligibility to proceed.

      Participants in all three arms of the trial will attend a baseline visit, a randomisation
      visit either one (genotype 3) or two (genotype 1) visits during treatment, an end of
      treatment visit and an SVR visit.

      All participants will be given incentives to continue with their treatment in the trial.
      These will consist of protein drinks and will be given at each study visit.

      Psychological intervention Participants randomised to fortnightly pick-up with psychological
      intervention will have an interview with the study nurse, prior to beginning their treatment,
      which will cover the educational intervention designed to aid their compliance with the drug
      regimen. The intervention will be based on the Information-Motivation-Behavioural (IMB)
      Skills Model of Adherence12 which was originally developed to explain adherence behaviour in
      HIV. Recent research suggests this model may have applicability in understanding the
      facilitator and barriers to adherence in HCV patients. The model suggests that provision of
      medication information, enhancing personal and social motivation and developing behavioural
      skills that are key determinants of adherence and may improve adherence in this group. The
      intervention will involve a structured interview in which the trial nurse and participant
      will develop an action plan that includes personalised information, sources of motivation for
      adherence and a treatment routine configured to be compatible with the participant's
      lifestyle. Anticipating barriers to adherence and problem-solving will be included in the
      treatment routine. The intervention will take place at the randomisation visit and last
      approximately one hour. During the intervention, participants will be guided by their trial
      nurse in the completion of a personalised booklet, "Hepatitis C and Me". The booklet contains
      general and personalised information on Hepatitis C, exercises designed to explore and
      enhance personal and social motivation for treatment adherence and a behavioural action plan
      (the skills element of the IMB model). The booklet uses the principles of node-link mapping
      to structure the intervention. Node link mapping use a set of visual tools to structure and
      guide therapeutic conversation and has been shown to enhance memory and compliance with
      treatment in substance misusers. Participants in the other two arms of the trial, who are not
      receiving the psychological intervention, will be given the current National Health Service
      (NHS) Tayside hepatitis information booklet ("Living with Hepatitis C") which provides
      generalised information about HCV without personalised information or specific strategies to
      enhance motivation and behavioural skills.

      Reinfection follow up. Trial participants will be invited to also consent for access to
      information from their annual clinic visits and HCV testing at any other contact with
      clinical services for up to 5 years, to detect re-infection.

      Illicit drug monitoring Illicit drug use will be recorded at baseline and at end of treatment
      (week 8 for genotype 3, week 12 for genotype 1). One sample of urine for toxicology will be
      taken during treatment. Those participants who fail to achieve SVR will be compared to
      successful participants for any correlation with particular substance use. For any candidate
      substance associated with failure to achieve SVR not explained by lack of adherence,
      biological samples will be analysed for biological mechanisms.

      Adherence monitoring Adherence of those participants randomised to DOT will be documented on
      a daily log. Those randomised to fortnightly collection of medication will receive Zepatier
      tablets in blister packaging. They will return their packets of medication every two weeks
      and any remaining tablets will be counted. Participants infected with HCV genotype 3 will
      additionally receive bottles containing Sovaldi tablets. These bottles will be fitted with
      adherence aid caps that record time and date of each cap opening.
    

Intervention name(s): Elbasvir/Grazoprevir 50 MG-100 MG Oral Tablet; Psychological intervention; Sofosbuvir 400 MG
Intervention type(s): Drug; Behavioral; Drug
Intervention description(s): Drugs will be given to participants to treat hepatitis C infection; Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, "Hepatitis C and Me". The booklet uses the principles of node-link mapping to structure the intervention.; Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection
Other intervention name(s): Zepatier; Sovaldi
Intervention MeSH terms: Sofosbuvir; Grazoprevir; Elbasvir-grazoprevir drug combination
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomised, un-blinded trial
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Illicit drug; Injecting drug