A systematic review and meta-analysis of community and primary-care-based hepatitis C testing and treatment services that employ direct acting antiviral drug treatments

Of the 71 million persons infected with HCV, 5.6 million (8%) currently inject drugs [1, 2]. The World Health Organization (WHO) has defined global targets for HCV diagnosis and treatment, which represents a major step towards the aim of global elimination by 2030 [3].

However, rates of uptake of HCV testing, linkage to care and treatment remain low across many countries [4]. Barriers to accessing funded Direct Acting Antiviral (DAA) drug treatment may be due to provider concerns regarding co-morbidities, adherence, and side effects management [5]. Social factors affecting treatment access have been categorised as social stigma, housing, criminalisation, health care providers’ attitudes and stigmatising practices, and gender [6]. Individuals may prioritise other needs and may be wary of the consequences of a diagnosis on their circumstances; health systems may present complex and rigid arrangements that must be navigated in order to access care [7]. The stigma associated with both injecting drug use and HCV infection is pervasive [8]. The concept of the care cascade has focussed attention on the performance of different pathways and the attrition of patients accessing testing, diagnosis, treatment and care [9].

It is common in many developed and developing countries, for specialist clinicians to provide HCV treatment, often from hospital outpatient facilities [10]. Recently, prescribing of DAAs has become common practice in many countries [10]. Treatment of HCV with these medicines is simple and well-tolerated [11]. The safety profile and high efficacy of DAAs means that HCV treatment can be delivered by a range of non-specialist clinicians including nurses, pharmacists and general practitioners, therefore providing enhanced access to virological cure (SVR) [12]. The ease of transferring care to community and primary care environments is assisted by the use of treatment regimens that do not contain ribavirin or interferon [13]. Progress with implementing treatment pathways provided by non-specialists in community and primary care environments has been identified as one of the key steps in the elimination of HCV [14]. The World Health Organization’s Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection promote simplified service delivery models: integration with other services; decentralised services supported by task-sharing; and community engagement, with the intention of reducing stigma and increase uptake of treatment [14].

This review was undertaken to identify rates of treatment uptake, treatment completion and achievement of sustained viral response for adults infected with hepatitis C using DAA-only treatment regimens in community and primary care-based care pathways, evaluated by studies using observational and experimental study designs. Studies that compared community-based treatment care pathways with specialist care were actively sought.

This systematic review was undertaken and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. The methods of analysis and defined inclusion criteria were specified in advance and documented in a study protocol. The study was registered in PROSPERO (CRD42017069873). The PICOS elements defined for this review are set out in Table 1.

The rationale adopted in the design of the PICOS elements was intended to provide some answers to the questions raised by the WHO Guidance and its recommendations for simplified and decentralised treatment delivery models, integrated with other services in community and primary-care environments [14]. Therefore a population over 18 years old was selected, as being less likely to have gained their infection through vertical transmission. Co-infected individuals with other blood borne virus infections were also excluded as their care was likely to be more complex, requiring specialist rather than simplified care. Studies from prison populations were excluded since these individuals lived in contained communities. Studies that utilised interferon and ribavirin-based treatment regimes as the primary intervention were also excluded, since monitoring and patient management requirements, made simplified and decentralised care less likely. Sustained viral response at 12 weeks (SVR12) was taken as a marker for virological cure; failure to achieve SVR may be attributed to both treatment failure and loss to follow-up [16]. Studies were restricted to the English language since study resources precluded any translation activities. Published studies were utilised including conference abstracts, in order to capture results from early studies when the first DAAs were introduced into practice.

This paper reviews evaluations of care pathways that utilise DAAs in a range of community and primary care settings. The WHO Guidelines on care and treatment of persons diagnosed with chronic HCV infection promote simplified service delivery models; integration with other services; decentralised services supported by task-sharing; and community engagement to address stigma and increase reach [14]. The studies considered in this systematic review and meta-analysis therefore provide some evidence for the extent of implementation of these guidelines.

The studies identified that met our inclusion criteria were grouped according to location: primary care; integrated health care systems (ECHO); opioid treatment centres; in pharmacies / pharmacist clinics; and through telemedicine. These care pathways acknowledged the need to provide local services with reach into the communities where people with hepatitis C live their lives.

In all three areas assessed in our study: uptake of treatment; completion of treatment; and attainment of SVR, a positive outcome was reported by all identified studies. This was seen across each of the distinct environments from which the care was provided. Since the positive outcomes were drawn from distinctly different pathways of care, further confidence might be inferred from this consistency of direction of effect. However, amongst the studies that met our inclusion criteria, there was a lack of studies using comparators from specialist centres. Data contained in these studies nevertheless demonstrated high uptake of treatment and high rates of attainment of SVR: among populations of vulnerable people who normally struggle to access care. Studies that did include comparators showed no significant differences in uptake or SVR. Several of the studies reported an increased uptake of treatment, but most reported equivalence. Some studies reported lower rates of attainment of SVR, because of study participants failing to undergo a confirmatory blood test post-treatment, within the study timelines. With DAAs SVR rates of greater than 97% are delivered if patients adhere to treatment, therefore completion of therapy can be a surrogate for SVR [16].

Previous systematic reviews have considered barriers and facilitators to care, as well as the views and experiences of people who inject drugs [7, 40]. These studies concluded that the target groups for HCV often had poor levels of knowledge about the infection and of the processes involved with testing and treatment. A fear of stigma and discrimination and a reticence to discuss risk behaviours tended to prevent engagement. These barriers could be addressed through educating participants, increasing awareness and redress of institutionalised stigma and integrating HCV treatment pathways into other services where the target group were likely to go.

Increased uptake of testing has been observed when testing is offered at the same time as other routine care [4]; with integrated services for both opioid users and with mental health services. There are advantages to targeting services at populations with predicted high prevalence of HCV [41]. Provision of HCV treatment as part of a directly observed treatment arrangement, increased attainment of SVR [42]. Achievement of these factors within local health systems needs to be commonplace if the WHO target for elimination is to be met [43]. There is some evidence that this is now happening [44].

The results from this systematic review highlight the lack of well-controlled randomised controlled trials and comparative studies, with just two randomised controlled trials identified and four cohort studies. While the publication of such studies is an important step in building confidence that decentralisation of hepatitis C treatment can be accomplished, the paucity of evidence reflects the difficulty in funding pathways to care studies and the relatively recent removal of the restrictions on the use of DAAs. Two further studies have been commenced identify that further evaluations of interferon-free treatments in primary care environments are underway [45, 46].

As with most systematic reviews, the quality of the studies and the heterogeneity of the study populations included in the analysis present a limitation of this study. The sensitivity analyses performed for our analysis did not have an impact on heterogeneity, meaning that an unexplained source of heterogeneity may be present. These difficulties may reflect the variety of ways in which patients can access HCV treatment. This may be positive and may be explained by the development of more patient centred pathways. These factors prevented a meta-analysis being achieved for many of the studies identified as eligible through the PICOS question defined for this review. Many of the studies that met the inclusion criteria were only available as conference abstracts at the time of review, including one of the randomised controlled trials. Nevertheless, over 10,000 participants were included in the identified studies. All studies had a consistent direction of effect, providing optimism that future evaluations will confirm with precision the effect size that should be delivered by simplifying treatment pathways and decentralising them to primary care. In terms of further limitations, we acknowledge limitations in the chosen methods for the systematic review, including potential publication bias to the findings by excluding non-English language studies; or any other biases introduced by our chosen inclusion and exclusion criteria.

This systematic review and meta-analysis identified studies which demonstrate the feasibility of decentralising care and providing local services with reach into communities of people infected with HCV. Such pathways may increase uptake of treatment and can provide sustained viral responses equivalent to those attained in specialist centres. Further studies are needed to confirm the promising start to the implementation of interferon-free treatment regimens. The successful implementation of such pathways to deliver successful patient outcomes is a key requirement for a “treatment as prevention” strategy as a pathway to elimination of HCV [47].