Direct-acting Antiviral Therapy and Reinfection Among PWID With Chronic HCV in Community-based Settings
Direct-acting Antiviral Therapy and Reinfection Among PWID With Chronic HCV in Community-based Settings
SHARP-C is an observational cohort study investigating the effect of direct-acting antiviral
 (DAA) therapy and reinfection in people with chronic hepatitis C virus (HCV) and recent
 injecting drug use. A prospective, observational cohort design will be used to enrol patients
 attending tertiary drug and alcohol and primary health care services.

 Participants will be prescribed a direct-acting HCV medication as per the standard of care.
 The on treatment phase will vary dependent on the type of a direct-acting antiviral
 prescribed as per the standard of care. Once patients have completed their treatment course
 they will be followed up every 3 months for up to 3 years following the end of treatment
 phase.

 The study will aim to evaluate the incidence of HCV reinfection following successful DAA
 treatment over the three years of follow up. The study will also evaluate the proportion of
 patients with undetectable HCV RNA at 12 weeks post end of treatment (SVR12) with
 direct-acting anti-viral HCV therapy.
In Australia, hepatitis C virus (HCV)-related morbidity and mortality have doubled in the
 past decade, with health care costs of $220 million per annum1. This is due to a large,
 ageing population with chronic infection (230,000), and low uptake of existing
 interferon-based therapy (1-2% per year) due to side-effects, and sub-optimal therapy
 efficacy. The majority of new (90%) and existing (80%) cases of HCV infection occur among
 people who inject drugs (PWID).

 In the community, 15-20% of current PWID report recent (last month) receptive needle/syringe
 sharing2. Qualitative research shows that decisions about sharing equipment are
 multi-factorial and can include issues ranging from service access (such as distance to
 service and opening hours), concerns about anonymity, perceptions that HCV is ubiquitous and
 unavoidable3 to socially-located concerns that promote use of sterile equipment such as a
 desire to avoid "track marks"4. There is no research that examines sharing of injecting
 equipment in those with successful therapy in either community or prison settings.

 Increasing access to HCV therapy is a key objective of national and NSW Hepatitis C
 Strategies5,6. The advent of well-tolerated, simple, oral hepatitis C virus (HCV) regimens -
 direct acting antivirals (DAAs) - has the potential to transform this landscape. These are
 much shorter, tolerable treatment regimens with cure >95%, providing an opportunity to
 reverse the rising burden of advanced liver disease. From 1st March 2016, these highly
 efficacious HCV therapies have been listed on the Pharmaceutical Benefit Scheme, and people
 with recent injecting drug use are eligible to receive them. This is an important feature of
 the listing. In many countries, people who have not ceased injecting drug use are ineligible
 to receive DAA therapy7, despite the fact that they comprise a significant proportion of HCV
 cases. Australia is therefore poised to lead the world in the scale-up of new therapies to an
 extent that many countries with such exclusions will not be able to achieve.

 This feature of DAA access also affords unique opportunities with respect to the
 implementation of treatment scale-up in community drug treatment clinics. Australia has good
 treatment coverage for people who are opioid dependent, with over 50% of opioid dependent
 people estimated to engage in opioid substitution therapy (OST) 8. Community-based drug
 treatment clinics represent another logical venue for expansion of HCV care beyond existing
 tertiary HCV treatment centres 9,10.

 Although response to DAA HCV therapy is high, lower responses have been observed among people
 with previous treatment experience9, cirrhosis9 and those with baseline or emergent
 resistance associated variants10. Such resistance associated variants can persist for up to
 two years after treatment11, affect re-treatment options12, and be transmitted to new
 hosts13. Further, PWID are likely to be exposed to multiple HCV infections as a result of
 ongoing high-risk behaviours and might commonly harbour mixed HCV infections (infection with
 two or more distinct viruses) 14. Underlying mixed HCV infection can contribute to
 nonresponse during therapy14, which has implications for DAA regimens that are preferentially
 active against specific viral genotypes or subtypes. These data argue for surveillance of HCV
 resistance and mixed HCV infection among PWID to resolve residual concerns regarding their
 clinical and public health significance.

 Two systematic reviews assessing interferon-based therapy for PWID have demonstrated
 responses comparable to randomised controlled trials excluding PWID15, 16. These data have
 supported international recommendations for the management of HCV for PWID 17. However, there
 are limited data on DAA therapy among recent PWID. As treatment is broadened to include more
 marginalised individuals, many clinicians are reluctant to treat HCV among PWID with recent
 injecting drug use with new DAA therapies. Major concerns include poor adherence/response,
 increased risk behaviour and HCV reinfection.

 A major concern is that ongoing injecting risk behaviours following DAA therapy in PWID will
 lead to HCV reinfection, reversing the benefits of cure. Ongoing risk behaviours following
 successful HCV therapy may lead to reinfection and compromised treatment outcomes14. In a
 systematic review and meta-analysis of HCV reinfection among PWID performed by the
 investigators, the pooled estimate of re-infection was 2.2/100 p-yrs (95% CI, 0.9-6.1)
 overall and 6.4/100 p-yrs (95% CI, 2.5-16.7) among individuals who reported injecting drug
 use post-SVR16. The one study of HCV reinfection post-therapy in prison performed to date was
 small (n=74), retrospective, and did not assess the rate of HCV reinfection18. Studies of
 reinfection following HCV therapy are limited by small sample sizes, retrospective study
 designs, incomplete follow-up, and a lack of sensitive methods to detect reinfection.
 Further, there are no data on HCV reinfection among recent PWID treated with DAAs.

 Although DAA therapy could limit HCV-related disease burden, as treatment is broadened to
 include more marginalised individuals, many clinicians are reluctant to treat HCV among
 recent PWID, given concerns about poor adherence (and lower response to therapy), increased
 risk behaviours (due to the ease and high cure rates of DAA HCV therapy) and HCV reinfection
 (thereby reversing cure). However, no data exist on the extent to which this should be a
 concern. Given that DAA HCV therapy is highly expensive, we urgently need data on the
 magnitude of risk for, and predictors of, HCV reinfection. It is also unclear whether PWID
 treated in these two settings will vary in their response to DAA therapy and risk for
 reinfection.

 The investigators have an excellent track record of conducting high quality cohort studies
 and clinical trials among PWID in the community19-23 and prison24, with high participant
 retention in follow-up. The investigators have developed a network of clinical sites
 providing HCV care in nine community-based drug treatment clinics20, 25. In SHARP-C the
 investigators will explore the risk of HCV reinfection and treatment efficacy among recent
 PWID with chronic HCV and recent injecting drug use.
Inclusion Criteria:

 1. Participants have voluntarily signed the informed consent form.

 2. Be ≥18 years of age on day of signing informed consent form.

 3. Have chronic HCV infection.

 4. Recent injecting drug use (previous 6 months).

 5. Eligible for DAA therapy as per the Pharmaceutical Benefits Scheme (PBS) criteria

 6. HIV-1 infected participants enrolled in the study must meet the following criteria:

 1. Have HIV infection documented by any licensed rapid HIV test or HIV enzyme or
 chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry
 (Baseline) and confirmed by a licensed Western blot or a second antibody test by
 a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen,
 or plasma HIV-1 RNA viral load.

 2. Be on HIV Antiretroviral Therapy (ART) for at least 4 weeks prior to study entry
 using an ART regimen that is allowable with the intended DAA regimen as
 determined by the current PI and the Liverpool drug interaction website
 (http://www.hiv-druginteractions.org/) OR be naive to treatment with any
 antiretroviral therapy (ART) with a baseline CD4 count of >200 and have no plans
 to initiate ART treatment while participating in this study and through to at
 least Follow-up Week 4.

 Exclusion Criteria:

 1) The participant must be excluded from participating in the trial if the subject is
 unable or unwilling to provide informed consent or abide by the requirements of the study.