Effectiveness of direct- acting antiviral therapy among Aboriginal and Torres Strait Islander peoples with HCV infection in Australia: A national real- world cohort (REACH- C)

Aboriginal and Torres Strait Islander peoples experience a disproportionate burden of hepatitis C virus (HCV) infection. This study assessed the effectiveness of direct-acting antiviral (DAA) therapy among Aboriginal peoples in the three years follow - ing universal access in Australia. REACH- C, a national multicentre prospective cohort study, evaluated HCV treatment outcomes from sequential DAA initiations across 33 health services between March 2016 and June 2019. DAA effectiveness was assessed by sustained virological response (SVR) in the total (full analysis set) and effective - ness (modified analysis set excluding those lost to follow- up) populations. Overall, 915 (10%) Aboriginal and 8095 (90%) non- Indigenous people commenced DAA therapy, of whom 30% and 16% reported current injecting drug use and 73% and 42% were treated in primary care, respectively. SVR in the total and effectiveness populations was 74% and 94% among Aboriginal people and 82% and 94% among non- Indigenous people, with loss to follow- up contributing to lower SVR in the total population anal - ysis (22% Aboriginal, 13% non- Indigenous). Among Aboriginal people, returning for follow- up was positively associated with older age (aOR 1.20; 95% CI 1.04, 1.39) and SVR was negatively associated with cirrhosis (aOR 0.39; 95% CI 0.19, 0.80) and prior DAA treatment (aOR 0.14; 95% CI 0.04, 0.49). Factors reflecting higher vulnerability or inequity were not associated with returning for testing or SVR. DAA therapy was highly effective among Aboriginal peoples with HCV treated through primary and ter - tiary services. Tailored community- led interventions are necessary to optimize follow-up and engagement. Sustained DAA uptake and equitable access to care, treatment and prevention are required for HCV elimination.


| INTRODUC TI ON
In 2016, the World Health Organization set the goal of 'elimination of viral hepatitis as a public health threat by 2030', 1 with the availability of direct-acting antiviral therapy (DAA) shifting the narrative in favour of HCV elimination. 2 Universal access to government subsidized DAA therapy has paved the way for elimination in Australia, with an estimated 49% of Australians living with HCV accessing DAA therapy between March 2016 and December 2019 following listing on the Pharmaceutical Benefits Scheme (PBS). [3][4][5] To achieve elimination, equitable DAA access and outcomes must be assured among key populations, including people who inject drugs and people in prison.
Indigenous peoples are another population requiring focussed attention given the disproportionate burden of HCV infection and potential inequalities in healthcare access. [6][7][8] Australia's Indigenous peoples, Aboriginal and Torres Strait Islander peoples (hereafter respectfully referred to as Aboriginal ∆ ), have been designated a priority population. 3,[8][9][10] Ensuring Aboriginal people have equitable access to safe and effective HCV care and treatment is essential for health outcomes and to achieve HCV elimination targets.
An estimated 21,584 Aboriginal people were living with HCV at the end of 2020, 11 accounting for 18% of people with HCV in Australia (n = 117,810) despite comprising 3% of the general population. 12 Increased prevalence of injecting behaviours facilitating transmission among Aboriginal people who inject drugs 13 and high rates of incarceration perpetuate a cycle of exposure to harm. 14,15 This is compounded by systemic disadvantages faced by Aboriginal peoples, including transgenerational trauma and historical exclusion from healthcare, a lack of culturally safe and specific services, and stigma and shame associated with HCV and injecting drug use. 16 The primary objective of this analysis was to assess DAA effectiveness among Aboriginal and non-Indigenous peoples with HCV infection in the three years following universal access in Australia.
Secondary objectives included evaluation of factors associated with returning for post-treatment follow up and achieving a sustained virological response (SVR).

| Study design, population and setting
REACH-C was a multicentre prospective cohort study among people with HCV infection who commenced DAA therapy between 1 March 2016 and 30 June 2019 at 33 health services in Australia (Table S1). 17 All people who commenced DAA therapy at each site were eligible and enrolled sequentially, with a waiver obtained for individual consent. There were no additional eligibility requirements and no exclusion criteria. The choice of DAA regimen and duration of treatment was at the discretion of the treating clinician, as part of routine care. Additional data were collected following SVR assessment for individuals who received DAA retreatment for posttreatment HCV RNA recurrence (treatment failure or reinfection). SVR was defined as HCV RNA below the lower limit of detection at least 12 weeks posttreatment. 18 Reinfection was defined as HCV RNA detected after achieving SVR or HCV RNA detected at SVR with an HCV strain distinct from the pretreatment strain (identified by genotype/subtype switch or sequencing if available). Reinfection was only reported at SVR or retreatment; reinfections occurring after SVR and which were not retreated at a REACH-C site were not reported. Virological failure was defined as HCV RNA detected at SVR assessment with the same genotype and/or subtype as pretreatment, unless identified as reinfection by sequencing. Individuals who discontinued treatment early with HCV RNA detected at the SVR assessment were classified as virological failure for the purposes of this analysis. An individual was considered lost to follow-up, if they did not have an HCV RNA test at or after 12 weeks posttreatment.

| Ethical approval
Ethical approval for the REACH-C study was obtained from: St

| Statistical analysis
Stratified by Aboriginal identification, baseline characteristics and treatment outcomes were described, with outcomes evaluated in Factors hypothesized to be associated with DAA effectiveness or return for follow-up were selected a priori and included sociodemographic (age, gender), clinical (liver fibrosis stage, HCV genotype, prior HCV treatment), behavioural (injecting drug use, OAT) and health service provision (service type, location). People who died prior to SVR were excluded from the analysis of factors associated with return for follow-up (n = 71). Statistical tests were twosided and performed at the 5% significance level unless specified otherwise. Analysis was conducted using STATA (version 15.0; Stata Corporation, College Station, TX). Of 9010 people included in this analysis, median age was 51 years, 69% were male, 23% had cirrhosis, and most had HCV genotype 1 (52%) or genotype 3 (40%) infection ( Table 1). Consistent with PBS availability during the study period, the most prescribed DAA regimen was sofosbuvir-ledipasvir (40%), with fewer people prescribed the pan-genotypic regimens, sofosbuvir-velpatasvir (21%) and glecaprevir-pibrentasvir (4%). Aboriginal people commencing DAA therapy were younger than non-Indigenous people (median age 43 vs. 52 years p < .001) and a higher proportion reported current injecting drug use (30% vs. 16%; p < .001). A higher proportion of Aboriginal people were treated through primary health services (73% vs. 42%; p < .001) and health services in regional or remote locations (50% vs. 38%; p < .001) compared to non-Indigenous people.

| Participant disposition
In the REACH-C cohort, the number of people initiating HCV treatment declined each year, with 50% treated in 2016 and 5% in 2019 ( Table 1). Over the study period, changes in key characteris-   (21) 680 (8) 870 (10) IDU + OAT 80 (9) 587 (7) 667 (7) OAT 97 (11) 836 (10) 933 (10) None 405 (44)  4910 (61)  5315 (59) Unknown 143 (16) 1082 (13) 1225 (14) HIV infection, n (%)  Among Aboriginal people, returning for follow-up was positively associated with older age and negatively associated with an unknown history of injecting drug use; current injecting drug use was not associated with returning for follow-up ( Table 2). Among non-Indigenous people, returning for follow-up was positively associated with older age, cirrhosis, prior interferon-based therapy and HIV co-infection and negatively associated with treatment at a primary health service and current injecting drug use and/or OAT ( Table 2). In adjusted analysis, Aboriginal identification was not associated with returning for follow-up (Table S2).
Among Aboriginal people, prior interferon-free DAA treatment and cirrhosis were associated with decreased odds of achieving SVR (Table 3). Among non-Indigenous people, female gender and receipt of OAT were associated with increased odds of achieving SVR, while older age, cirrhosis, nongenotype 1 infection and treatment in a regional or remote setting were associated with decreased odds of SVR ( Table 3). There was no association between achieving SVR and Aboriginal identification (Table S4).
Of those who returned for follow-up and did not achieve SVR

| DISCUSS ION
In this well-characterized national cohort enrolled from diverse cirrhosis) or 'difficult to reach' (i.e. people who inject drugs, people living in regional and remote settings). 18,19 Importantly, a more

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.