A Direct obserVed therApy vs fortNightly CollEction Study for HCV Treatment - ADVANCE HCV Study

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.