Abstract: We identified 28 studies (21 published, 7 unpublished): 13 from North America, 5 from the UK, 4 from continental Europe, 5 from Australia and 1 from China, comprising 1817 incident HCV infections and 8806.95 person-years of follow-up. HCV incidence ranged from 0.09 cases to 42 cases per 100 person-years across the studies. We judged only two studies to be at moderate overall risk of bias, while 17 were at serious risk and 7 were at critical risk; for two unpublished datasets there was insufficient information to assess bias. As none of the intervention effects were generated from RCT evidence, we typically categorised quality as low. We found evidence that current OST reduces the risk of HCV acquisition by 50% (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.40 to 0.63, I2 = 0%, 12 studies across all regions, N = 6361), but the quality of the evidence was low. The intervention effect remained significant in sensitivity analyses that excluded unpublished datasets and papers judged to be at critical risk of bias. We found evidence of differential impact by proportion of female participants in the sample, but not geographical region of study, the main drug used, or history of homelessness or imprisonment among study samples. Overall, we found very low-quality evidence that high NSP coverage did not reduce risk of HCV acquisition (RR 0.79, 95% CI 0.39 to 1.61) with high heterogeneity (I2 = 77%) based on five studies from North America and Europe involving 3530 participants. After stratification by region, high NSP coverage in Europe was associated with a 76% reduction in HCV acquisition risk (RR 0.24, 95% CI 0.09 to 0.62) with less heterogeneity (I2 =0%). We found low-quality evidence of the impact of combined high coverage of NSP and OST, from three studies involving 3241 participants, resulting in a 74% reduction in the risk of HCV acquisition (RR 0.26 95% CI 0.07 to 0.89). OST is associated with a reduction in the risk of HCV acquisition, which is strengthened in studies that assess the combination of OST and NSP. There was greater heterogeneity between studies and weaker evidence for the impact of NSP on HCV acquisition. High NSP coverage was associated with a reduction in the risk of HCV acquisition in studies in Europe.

Plain-language summary: We identified 28 research studies across Europe, Australia, North America and China. On average across the studies, the rate of new hepatitis C infections per year was 19.0 for every 100 people. Data from 11,070 people who inject drugs who were not infected with hepatitis C at the start of the study were combined in the analysis. Of the sample, 32% were female, 50% injected opioids, 51% injected daily, and 40% had been homeless. Our study was funded by the National Institute of Health Research's (NIHR) Public Health Research Programme, the Health Protection Research Unit in Evaluation of Interventions, and the European Commission Drug Prevention and Information Programme (DIPP), Treatment as Prevention in Europe: Model Projections. Current use of OST (defined as use at the time of survey or within the previous six months) may reduce risk of acquiring hepatitis C by 50%. We are uncertain whether high coverage NSP (defined as regular attendance at an NSP or all injections being covered by a new needle/syringe) reduces the risk of becoming infected with hepatitis C across all studies globally, but there was some evidence from studies in Europe that high NSP coverage may reduce the risk of hepatitis C infection by 76%. The combined use of high coverage NSP with OST may reduce risk of hepatitis C infection by 74%. Quality of evidence ranged from moderate to very low because none of the studies used the gold standard design of randomised controlled trials.