Hepatitis C virus (HCV) is a global health problem affecting around 58 million people worldwide (1). It is estimated that 7.2 million people will die from this disease between 2015 and 2030 (2). The introduction of direct-acting antivirals (DAAs) in 2013 has made HCV a curable chronic viral infection. DAAs have shown cure rates in real-world settings of over 95% with an 8- to-12-week once daily treatment with few or no side effects (3–5).

Hepatitis C virus elimination is now a possibility, which led the World Health Organization (WHO) to propose a global strategy aimed at eliminating HCV as a public health threat by 2030 (2). The current approach to achieving this goal is to target efforts to priority populations among whom HCV prevalence and incidence are high (6). Examples of these populations are people who inject drugs (PWID), men who have sex with men (MSM), and Indigenous people (3).

Each priority population has its own individual characteristics and faces distinct challenges, which impact its ability to access DAAs. PWID–especially female PWID–have reported stigma and discrimination, including in healthcare settings (7, 8). Homelessness, limited geographical access to HCV care, and criminalization of injection drug use (IDU) are other obstacles identified among PWID that could hinder their HCV treatment access (7). For MSM, unprotected anal intercourse, group sex, and the use of drugs during sex are sexual behaviors that have been associated with an increased risk of HCV infection (9–11). The incidence of HCV infection and re-infection remain particularly high among human immunodeficiency virus (HIV)-positive MSM (11–13). In Canada, Indigenous people experience five to 11 times higher HCV infection rates when compared to non-Indigenous people (12, 14). IDU, HCV-related stigma, and the impacts of colonization and intergenerational trauma are some of the main HCV treatment barriers for Indigenous peoples (12, 14–16). Being HCV-positive has been associated with greater mortality among Indigenous people especially among women (17–19).

There is a call for developing strategies tailored to key populations' needs (6, 7). Improving DAA uptake is increasingly seen as the critical step in the HCV care cascade, as a decrease in treatment initiation rates might prevent countries like Canada from achieving the WHO targets by 2030 (20). Previous systematic reviews have been published elsewhere. However, some include pre-DAA interventions (21) and others have focused on PWIDs or prisoners only (21, 22). The purpose of this systematic review was to map DAA-era interventions aimed at improving HCV uptake among a broad range of priority populations (e.g., PWID, MSM, Indigenous peoples and women). We focused on high- and middle-income countries to parallel the healthcare setting in Canada, as this review aims to inform HCV elimination efforts in this country.

This systematic review was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (23). The protocol was registered on PROSPERO (CRD42020158607).

Instead of creating population-wide interventions, developing population-specific approaches to improve HCV care access has been proposed as the path to eliminate this chronic viral infection (6). The present systematic review examined a wide variety of databases, sources and types of studies to identify existing interventions or strategies designed to improve HCV treatment initiation among women, PWID, MSM, and Indigenous peoples focusing on high- and middle-income countries.

We identified interventions in the current literature and organized them depending on their targeted stakeholder group (see Table 1). The most commonly implemented interventions were care co-ordination for patients, multidisciplinary teams for healthcare providers, and colocation of HCV care in community settings for the healthcare system. These interventions address a wide variety of obstacles faced by all subpopulations alike, such as stigma, gaps in the continuity of care, limited geographical access and homelessness (7, 71). Our results also reflect that there is an interest in offering decentralized HCV care by placing services as close as possible to HCV patients. This indicates that HCV care is taking a similar direction as in other infectious diseases, like HIV (72) and tuberculosis (73), in which decentralized care has proven to be an effective way to engage key populations.

The majority of studies described strategies that combined more than one intervention, suggesting that complex interventions are a common approach to promote and support HCV treatment initiation in priority populations. However, since the included studies were not designed to test the effectiveness of individual components, it is unclear if there is an additive or synergistic effect of implementing all components of these complex interventions compared to simpler individual strategies.

Few studies had control groups. Most of the uncontrolled studies reported a DAA uptake rate that was greater than for the general population, estimated to be below 20% (19, 74–79); however, their interventions were implemented in heterogeneous ways and are being evaluated without robust research designs. As a consequence, the integration of these studies' findings, for instance in meta-analyses, is difficult and may create uncertainty about which strategies to prioritize. More controlled studies are thus needed when evaluating interventions to improve DAA initiation. Such results would be critical to inform modeling and selection of strategies for countries to implement HCV elimination programs.

Direct-acting antiviral universal access appeared to be another fundamental intervention. Indeed, some interventions' impact on HCV treatment uptake was negatively affected by the absence of a universal DAA access policy. However, this system-based intervention seems to have a limited impact over time. Although removing fibrosis restrictions for DAAs appears to be an important step to improve HCV treatment initiation, HCV treatment uptake decreases 1 year following DAA universal access (19, 65). Therefore, additional interventions are needed to maintain high HCV treatment uptake rates after DAA universal access is implemented. A combination of interventions targeted to patients, healthcare providers, and the allocation of HCV services is likely to be an effective strategy to maintain DAA universal access impact over time.

Our systematic review focused on identifying interventions to improve DAA uptake, as this HCV care cascade step is critical in achieving the WHO HCV elimination targets (20). However, achieving such targets also requires an efficient system capable of identifying people living with HCV. Thus, all interventions identified in the present review need to be implemented in the context of strong HCV screening programs. Other systematic reviews have identified HCV screening interventions, such as practitioner-led testing, prioritizing testing in primary care and community settings, and provider education (80, 81), all of which can be implemented in conjunction with the interventions identified in the present review.

This review indicated that most scientific research on HCV interventions for increasing DAA uptake is concentrated in high-income countries. More investigation in this area is needed in middle-income countries. Finally, most research on interventions to improve DAA initiation is conducted with PWID. While it is true that PWID are at high risk of HCV infection (82), in practice, priority populations overlap (e.g., an Indigenous patient may inject drugs) and may experience “intersectional stigma” (83). Therefore, further interventions should specifically address and be tailored to other populations, such as women, MSM, and Indigenous peoples.

This systematic review has limitations. One concerns the screening process, specifically, the exclusions of abstracts that did not explicitly mention the populations of interest. As a consequence, we may have missed some potentially relevant studies. For instance, interventions not specifically targeted at the populations of interest or those studied at a general populational level were excluded. However, this was a choice that allowed us to successfully answer our review question and still provide a comprehensive portrait of interventions aimed at improving HCV initiation among a broad range of priority populations. Another limitation was the inability to retrieve the full text of conference abstracts despite contacting their authors, which represent 56% (22/39) of selected studies. Hence, the description of many interventions was restricted by the word limits of conference material. Nevertheless, including conference abstracts improved the comprehensiveness and precision of this knowledge synthesis (25). Finally, the inclusion of articles written only in English is a limitation, as some interventions may not have been captured.

In conclusion, the identified interventions were directed to three types of stakeholders: patients, care providers, and the healthcare system. Universal access to DAAs appears to be a critical first step but is not sufficient to maintain uptake. The combination of two or more interventions appears to be a common approach to promote DAA initiation. While some interventions seem promising, estimated effectiveness was quite variable and methodologic limitations prevented conclusions about what strategies might be most valuable to scale up. Specifically, we identified three research gaps, a lack of: (1) controlled studies estimating the individual or combined effects of interventions on DAA treatment initiation rates; (2) studies in middle-income countries; and (3) investigation of interventions tailored to women, MSM, and Indigenous people. This systematic review provides a portrait of existing strategies to support DAA uptake. We hope its findings will provide a roadmap for stakeholders (e.g., patient partners, researchers, clinicians, quality improvement agents, and policymakers) to design, study, report and implement new interventions to ultimately meet WHO goals to eliminate HCV infection.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

MK obtained the funding for the present work. MK and BL conceived the current review. TE designed the search strategy and provided substantial methodological support. DO-P and AA performed the studies selection, data extraction, and evidence synthesis. DO-P drafted the manuscript. AA, TE, KE, BL, and MK reviewed the manuscript, provided feedback, and approved the final version. MK supervised the present work. All authors have participated sufficiently to take public responsibility for its content.

MK has received funding through the Gilead LEGA-C NoCo Program [Grant number IN-US-334-4492, June 1st 2018] for the development of this investigator-initiated study.

This study received funding from the Gilead LEGA-C NoCo Program. The funder had the following involvement with the study: revision of the manuscript. MK reports grants for investigator-initiated studies from ViiV Healthcare, Merck, and Gilead; consulting fees from ViiV Healthcare, Merck, AbbVie and Gilead. She is supported by a Canada Research Chair, Tier 1. BL is the holder of a Canadian Institutes for Health Research, Strategy for Patient-Oriented Research Mentorship Chair in Innovative Clinical Trials for HIV Care and also supported by a career award, LE 250, from the Quebec's Ministry of Health for researchers in Family Medicine. BL reports grants for investigator-initiated studies from ViiV Healthcare, Merck, and Gilead; consulting fees from ViiV Healthcare, Merck, and Gilead. DO-P, AA, TE, and KE have no conflicts of interest to declare.

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