High Effectiveness of Broad Access Direct-Acting Antiviral Therapy for Hepatitis C in an Australian Real-World Cohort: The REACH-C Study

Australia was one of the first countries with unrestricted access to government subsidized direct-acting antiviral (DAA) therapy for adults with chronic hepatitis C virus. This study assessed real-world DAA treatment outcomes across a diverse range of Australian clinical services and evaluated factors associated with successful treatment and loss to follow-up. Real-world Effectiveness of Antiviral therapy in Chronic Hepatitis C (REACH-C) consisted a national observational cohort of 96 clinical services including specialist clinics and less traditional settings such as general practice. Data were obtained on consecutive individuals who commenced DAAs from March 2016 to June 2019. Effectiveness was assessed by sustained virological response ≥12 weeks following treatment (SVR) using intention-to-treat (ITT) and per-protocol (PP) analyses. Within REACH-C, 10,843 individuals initiated DAAs (male 69%; ≥50 years 52%; cirrhosis 22%). SVR data were available in 85% (9,174 of 10,843). SVR was 81% (8,750 of 10,843) by ITT and 95% (8,750 of 9,174) by PP. High SVR (≥92%) was observed across all service types and participant characteristics. Male gender (adjusted odds ratio [aOR] 0.56, 95% confidence interval [CI] 0.43-0.72), cirrhosis (aOR 0.52, 95% CI 0.41-0.64), recent injecting drug use (IDU; aOR 0.64, 95% CI 0.46-0.91) and previous DAA treatment (aOR 0.50, 95% CI 0.28-0.90) decreased the likelihood of achieving SVR. Multiple factors modified the likelihood of loss to follow-up including IDU ± opioid agonist therapy (OAT; IDU only: aOR 1.75, 95% CI 1.44-2.11; IDU + OAT: aOR 1.39, 95% CI 1.11-1.74; OAT only, aOR 1.36; 95% CI 1.13-1.68) and age (aOR 0.97, 95% CI 0.97-0.98). Conclusion: Treatment response was high in a diverse population and through a broad range of services following universal access to DAA therapy. Loss to follow-up presents a real-world challenge. Younger people who inject drugs were more likely to disengage from care, requiring innovative strategies to retain them in follow-up

Retreatment for hepatitis C virus direct-acting antiviral therapy virological failure in primary and tertiary settings: The REACH-C cohort

Virological failure occurs in a small proportion of people treated for hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapies. This study assessed retreatment for virological failure in a large real-world cohort. REACH-C is an Australian observational study (n = 10,843) evaluating treatment outcomes of sequential DAA initiations across 33 health services between March 2016 to June 2019. Virological failure retreatment data were collected until October 2020. Of 408 people with virological failure (81% male; median age 53; 38% cirrhosis; 56% genotype 3), 213 (54%) were retreated once; 15 were retreated twice. A range of genotype specific and pangenotypic DAAs were used to retreat virological failure in primary (n = 56) and tertiary (n = 157) settings. Following sofosbuvir/velpatasvir/voxilaprevir availability in 2019, the proportion retreated in primary care increased from 21% to 40% and median time to retreatment initiation declined from 294 to 152 days. Per protocol (PP) sustained virological response (SVR12) was similar for people retreated in primary and tertiary settings (80% vs 81%; p = 1.000). In regression analysis, sofosbuvir/velpatasvir/voxilaprevir (vs. other regimens) significantly decreased likelihood of second virological failure (PP SVR12 88% vs. 77%; adjusted odds ratio [AOR] 0.29; 95%CI 0.11–0.81); cirrhosis increased likelihood (PP SVR12 69% vs. 91%; AOR 4.26; 95%CI 1.64–11.09). Indigenous Australians had lower likelihood of retreatment initiation (AOR 0.36; 95%CI 0.15–0.81). Treatment setting and prescriber type were not associated with retreatment initiation or outcome. Virological failure can be effectively retreated in primary care. Expanded access to simplified retreatment regimens through decentralized models may increase retreatment uptake and reduce HCV-related mortality

Correlates of infection outcome following multiple exposures to the Hepatitis C virus

Exposure to HCV genotypes 1 and 3 is common but cross-protection between these two genotypes is not well understood and likely to be limited. An important correlate of HCV infection outcome is the host’s immune response and the virus’ adaptation to these responses. However, the ability to measure successful immune responses against HCV is dependent on our choice of antigenic targets relevant for different host Human Leucocyte Antigen (HLA) types. Given the bias in published HCV epitopes for a few common HLA types and genotype 1, we undertook a population-based genetic approach to identify in-vivo immune targets for HCV genotypes 1 and 3. This genetic study revealed a number of putative novel immune targets for both genotypes, but importantly only few were in common. From this list, predicted HCV epitopes were designed to examine HCV genotype immune responses (specific and cross-protective) in individuals with haemophilia who were exposed to multiple HCV genotypes via contaminated blood products. Accordingly, individuals in this cohort that remain HCV RNA-negative demonstrate the signature of a successful multi-genotype control. On the other hand, individuals that develop chronic infection may have successfully suppressed at least one genotype but are still chronically infected with another. Individualised IFN-gamma ELISpots accounting for an individual’s HLA type, HCV sequence and using the predicted epitopes (including wildtype and escape variants) were performed on 32 individuals with chronic infection and 30 individuals who had resolved infection (spontaneous/therapy). Importantly, individuals with chronic HCV infection with one genotype exhibit genotype specific T-cell responses against the alternative genotype, likely reflecting successful immune control of at least one genotype. Conclusion: The identification and functional analysis of biologically relevant genotype-specific T-cell responses in this cohort of individuals will provide critical insights for the understanding of HCV resolution in the setting of multi-genotype exposure. It will also provide the basis for the development of therapeutic strategies to combat HCV infection, including an effective vaccine directed against HCV genotypes