Hepatitis C models of care: approaches to elimination

Abstract

Hepatitis C direct-acting antivirals (DAAs) have an efficacy of 95% or greater, with pangenotypic options. Many regions in Canada have recently abolished the need to demonstrate fibrosis before treatment with DAAs, and several combination therapies are available under public and private insurance coverage. As a result, efforts to increase treatment are largely focused on engaging specific populations and providers. With minimal side effects and decreased need for monitoring, hepatitis C screening, linkage, and treatment can largely be done in a single setting. In this article, we highlight both Canadian and international examples of the specialist’s ongoing role and discuss the task shifting of hepatitis C treatment to primary care; specialized community clinics; and mental health, corrections, addictions, and opioid substitution therapy settings. Although specialists continue to support most models of care described in the literature, we highlight the potential for non-specialist care in working toward the elimination of hepatitis C in Canada.

Introduction

Historical perspective

Although therapy for hepatitis C virus (HCV) has evolved rapidly in recent years, this rate of progress has not always been the norm. Even before the discovery of the virus in 1989, small studies evaluated the use of injectable interferon to treat transfusion-acquired non-A, non-B hepatitis (1). Early success rates were dismal, with fewer than 10% of those treated showing a response. Over the next two decades, interferon remained the backbone of treatment. Although sustained virologic response (SVR) rates increased incrementally, even with optimal peginterferon and ribavirin, fewer than 50% of patients were cured, and therapy was very difficult (2). Treatment side effects were often debilitating and interfered with work, relationships, and quality of life; and many people, particularly those with other medical or mental health comorbidities, were simply not candidates for interferon-based treatment (3). It was in this context that treatment was relegated to specialty clinics led by experienced providers with models of care that reflected this complexity.

Evolution of care: from the specialist to community

Traditional HCV models of care

During the interferon years, the decision to treat someone with HCV infection had to be justified. For those with minimal liver injury without other HCV-related complications, treatment with interferon was simply not worth the risk. This balance of risk versus benefit led to fibrosis restrictions for access to therapy. As such, most patients underwent a liver biopsy to stage liver fibrosis. If at least moderate liver damage was present and a decision to proceed with therapy was made, careful protocols were put in place to ensure there was adequate oversight of therapy. Frequent laboratory monitoring and regular visits were required to assess and manage treatment toxicity and to determine the effectiveness and duration of therapy.

Over the prolonged interferon era, clinics relied on highly qualified staff with extensive treatment experience and using carefully developed protocols. These requirements for intensive monitoring served as a major barrier to entry for practitioners without a large number of people with HCV in their practice. The potential for toxicity, particularly neuropsychiatric side effects, also led many treaters to limit treatment access for those with a history of pre-existing mental illness or substance use (4). Practically, these issues limited the numbers of individuals who could be treated, which is unfortunate considering that HCV disproportionately affects these priority populations.

The models of care for interferon-based therapy were necessarily arduous and comprehensive. The introduction of the first-generation direct-acting antivirals (DAAs) actually made things more challenging. Telaprevir and boceprevir were combined with peginterferon and ribavirin. Although SVR rates increased, additional side effects from these new agents along with the need for sensitive HCV RNA assays to determine treatment response made therapy even more complicated (5). Fortunately, these regimens were quickly replaced by all-oral, highly effective, and extremely well-tolerated DAAs. Although it initially made sense to maintain the careful, specialist-led models of care, it quickly became clear that treatment with DAAs does not require the same oversight as treatment with interferon (6). In addition to increased tolerability and efficacy, treatment options are shorter, often pangenotypic, require less monitoring, and are easier to deliver, even among those with extensive medical comorbidities (Figure 1).

Figure 1:

Comparison of past- with present-day hepatitis C treatment

Note: Changes to hepatitis C therapeutics and prescribing policies allows for more individuals to be treated by solo providers or small teams and with little monitoring or on-treatment changes to therapy. This is in contrast to interferon-based therapy, which required multidisciplinary teams with specialist oversight and close monitoring.

NP = nurse practitioner

Simplification increases the capacity of existing treaters and makes it easier for novice providers to enter the field. Perhaps most important, the ability to move away from specialist-led, hospital-based treatment models creates opportunities to engage individuals with HCV in care, particularly individuals who may not be comfortable in traditional health care settings. Ultimately, reaching and engaging all those with HCV in care will be critical to national, regional, and global elimination efforts.

Specialist care

Although DAAs allow many people to be successfully treated without ever seeing a hepatologist or infectious diseases physician, specialists continue to play an important role in the delivery of HCV care. However, the role of the specialist should change. Continuing to use models developed for interferon-based therapy in the DAA era is inefficient and risks underusing the expertise of experienced HCV treatment providers. Rather than evaluating all individuals living with HCV, specialists and their teams should change the focus of their efforts. People with advanced liver disease, those with complicated medical comorbidities, and those who have not responded to initial courses of HCV therapy may benefit from specialist care to optimize outcomes.

Specialized hepatology care is particularly important for those with decompensated cirrhosis. Although treatment may still be effective for those with very advanced liver disease, problems can arise during treatment, including the need for urgent liver transplantation. Involvement of specialists may be prudent for anyone with cirrhosis, at least until non-specialists are very comfortable with HCV therapy and the complications that may arise. Specialists can also serve an important educational role for providers entering the HCV field.

Project ECHO (Extension for Community Healthcare Outcomes) was initially developed to provide HCV care to people in underserved areas of New Mexico (7). Rather than have individuals travel great distances to see providers at the university-affiliated hospital, Project ECHO enables local providers to deliver high-quality care with oversight and mentoring from a central team. The hub-and-spoke model connects remote providers to a multidisciplinary team with expertise in all aspects of HCV care by means of simple video-conferencing platforms. Weekly sessions involve a short didactic presentation on a particular aspect of HCV care, followed by case presentations from the community sites. Cases are discussed with all participants, ensuring that all participants have the opportunity to learn from each case presented. An important aspect is that not only the hub experts offer management advice; participants at every site are encouraged to ask questions and offer suggestions on management. In many cases, community sites have highly relevant expertise in areas related to HCV care, such as management of substance use disorders and mental health (8).

Project ECHO was developed in the interferon era and demonstrated equivalent treatment outcomes between those treated at the university clinic and those treated in rural areas of New Mexico by primary care providers (PCPs; 7). It has expanded around the world, including to Canada. Numerous provinces have established ECHO models for care of people with HCV and other chronic diseases, with very positive outcomes. Although highly effective, Project ECHO is still underused in Canada, limiting its impact. Other educational opportunities in which specialists play a large role include the development and maintenance of national and regional guidelines as well as national action plans. These educational leadership priorities often involve political action and advocacy around policy changes.

In addition to complicated case management and mentoring, specialists have an important role to play in outreach and screening. Initiation of large screening programs, such as those in emergency departments, requires champions and leadership (9). Although PCPs may carry out much of the screening, the design and implementation of initial programs require specialist input. Which screening test is optimal for a specific setting is an important determinant of the outcome of screening efforts. The key roles of specialist HCV providers are summarized in Figure 2.

Figure 2:

Shared role of specialist and non-specialist providers in the linkage to care and cure for those with chronic HCV

Note: Community and facility providers are more likely to identify HCV infections in primary care and in high-risk difficult-to-reach populations such as OST clinics, SISs, mental health facilities, and corrections. Treating individuals in their home clinic where they are diagnosed or in a setting they frequent and in which they feel comfortable is likely to increase SVR rates, with multiple models of care emerging. Specialists, however, continue to play an important role in the clinical management of those with decompensated cirrhosis, those with complex treatment failures, or those who have both HCC and HCV. Specialists also lead large screening programs and educational programs such as ECHO, develop guidelines, and improve diagnostic and treatment algorithms to decrease community or facility provider barriers. HCV = Hepatitis C virus; SIS = Supervised injection site; OST = Opioid substitution therapy; NP = Nurse practitioner; ECHO = Extension for Community Healthcare Outcomes; HCC = Hepatocellular carcinoma; ID = Infectious diseases; SVR = Sustained virologic response

Primary care

Preventive health in primary care includes screening for largely asymptomatic diseases, including HCV. Although HCV has a long list of risk factors, in Canada many individuals diagnosed with HCV report no known HCV risk factors and are largely or entirely asymptomatic. It is therefore difficult for providers to identify whom to screen, and more widespread screening strategies are warranted. As such, the recently published Canadian Clinical Practice Guidelines on HCV recommend screening by birth cohort, to include one-time screening of anyone born between 1945 and 1975 (10). In the United States, this widespread secondary prevention strategy, when added to other laboratory investigations, has shown a decrease in barriers to screening implementation in primary care by simplifying screening indicators and decreasing the need for additional blood draws (11).

In addition to screening the Baby Boomer cohort, PCPs are also well suited to work with clients who may have either previous or ongoing risk factors, and they are often the first point of contact in the health care system for newcomers to Canada. This is important because HCV screening is not part of the medical test list for those who have immigrated to Canada, despite its inclusion in newcomer screening guidelines for individuals from endemic countries (10,12,13).

Clients who may have other life experiences that have put them at risk, such as past or current injection drug use, high-risk sexual encounters, or incarceration, benefit from the stability and consistency of a PCP. This relationship, largely built on trust, increases the likelihood that the client will return for follow-up visits. Wait times and out-of-pocket expenses may also deter this population during HCV work-up and treatment in tertiary settings (14). PCPs are also an attractive option in rural and remote regions in Canada that have a high HCV burden (15).

A recent study in the United Kingdom demonstrated that only 38% of individuals referred to a specialist commenced treatment (16). Primary care has been identified as an opportunity to engage individuals known to be HCV positive in the care cascade. Although individuals may not attend specific HCV appointments, they may want to be seen for other acute episodic reasons or they may attend clinic in the context of an appointment for a family member, thus allowing the PCP to re-engage the client in HCV care. This includes HCV treatment readiness and work-up as well as vaccinations and transmission prevention counselling (17). Primary care also has the added benefit of a multidisciplinary team, allowing for motivational interviewing from nurses, social workers, and dietitians; increasing the possibility of altering modifiable risk factors for liver disease such as alcohol and substance consumption; and working toward a liver-healthy diet (18,19).

In the current era of DAA therapy, task-shifting HCV treatment to PCPs who have an interest in HCV allows clients to be treated in their home clinic, potentially decreasing rates of loss to follow-up. Online educational programs have assisted in supporting community treaters and have been shown to be cost-effective (7,20–22). Australia has recently quantified the number of non-specialists treating people with HCV. In 2016, of the 32,400 individuals receiving HCV treatment, on average 19% were being cared for by general practitioners (GPs) or nurse practitioners (NPs), nearly quadrupling during the 1-year collection time frame (from 8% to 32%; 23). Several other countries have also embraced this model, including the United States and Germany. Previously shown to work in underserved regions in the United States (24), task shifting was recently evaluated among GPs and NPs in primary care. In the ASCEND study, 600 patients either stayed in specialty care for treatment or went back to their primary GP or NP. Of the 600 participants, 516 achieved SVR at a rate of 89% for NPs, 87% for GPs, and 84% for specialists. Visit attendance was also significantly higher among community providers, and patient loss to follow-up was thought to be a contributing factor to non-SVR (25). Additional studies are required to further elucidate safety and efficacy of treatment in primary care, including demonstrating the choice of appropriate DAA combination and treatment length.

In Canada, PCP-specific barriers to rolling out HCV treatment in primary care exist. For example, Canada continues to have province-specific DAA prescribing restrictions for non-specialists, which decreases opportunities for linkage to GPs and NPs in primary care. Models of provider reimbursement, or the lack thereof, and the need for additional training and education may also dissuade PCPs from engaging in treatment. Yet, in the context of widespread screening and linkage to cure, PCPs are likely the most economical and efficient mechanism by which to work toward HCV elimination. Further demonstration of the clinical and cost effectiveness of this model may increase ongoing interest in implementing HCV care in training programs and provider role creation and incentivization.

Treat where identified: Cure among current or former people who inject drugs and street-involved or difficult-to-reach individuals

During the interferon treatment era, certain circumstances precluded individuals from receiving treatment, most notably mental health concerns or active substance use. However, studies have now clearly demonstrated that neither mental health concerns nor substance use greatly affect treatment outcomes. Multiple studies have shown high treatment completion and SVR rates among individuals receiving opiate agonist therapy (26,27). More recently, a multicentre study enrolled 103 participants who were actively injecting, of whom 100 completed therapy with 94% SVR (28).

In addition to the tolerability and efficacy of treatment, novel diagnostic strategies have also increased engagement in the care cascade. Point-of-care and dried blood spot (DBS) antibody as well as RNA testing allow for diagnosis without the need for phlebotomy, a major barrier for those with a history of past or current injection drug use (29). Despite these advances in diagnostic streamlining and increased cure rates, engagement after diagnosis continues to be a major gap (30). Although the exact mechanism of HCV acquisition may not be clear, people who inject drugs (PWIDs), people who are street involved or low income, or people who are difficult to reach for other reasons often experience both structural and geographic challenges to obtaining care.

Specialized community-based HCV treatment

Integrated community-based centres that offer diagnostic and treatment services are designed to increase access to HCV services through incentivized education programs, mental health support, peer or harm reduction staff, and extensive outreach. However, although many programs offer on-site primary care, they do not necessarily provide opioid substitution therapy (OST). Although each program is unique, high treatment and cure rates have been observed in real-world studies reporting anywhere from 80% to 89% SVR (31–34). Although few studies assess outcomes other than SVR, a 2015 Toronto-based study by Mason et al reported improved non-HCV outcomes, such as significant improvement in housing and obtaining government income assistance, as a result of engagement in HCV services (35). In Canada, provincial models have also been developed to streamline referrals, triage, and intake, often consisting of care coordinators and HCV specialists. Persons enrolled in these studies also had high SVR rates (97.6%; 36). Although not extensively described in the literature, privately funded, publicly accessible HCV treatment programs are also a mechanism to improve wait times for specialty care. These centres increase access in mid-sized urban settings that may not have large academic specialty services.

Facility-based treatment

Inpatient mental health

Individuals who struggle with severe and persistent mental illness have a higher rate of HCV than the general population. In 2016, Hughes et al reported a pooled HCV antibody prevalence of 17.4% among 13 inpatient mental health sites in North America, in comparison with a hepatitis B prevalence of 2.2% and HIV prevalence of 6% (37). Other single-country studies have also found rates among inpatients with severe and persistent mental illness to be well above the national average (38,39). Despite this evidence, opt-in or opt-out testing has not been described in the literature, nor has whether individuals are engaged in the care cascade during their stay or after discharge.

In 2011, an Australian group published that physicians working with psychiatric clients underestimated the prevalence of HCV and generally did not feel well informed about HCV (40). However, since the use of all-oral DAAs, similar studies have not been conducted. In addition, few studies have assessed the success of newer 8- to 12-week therapy options during psychiatric admissions. Considering that most medications taken on inpatient mental health units are observed, the lack of treatment (or literature demonstrating these successes) leads to missed opportunities to cure persons with severe and persistent mental health challenges.

Corrections

Correctional systems have some of the highest HCV prevalence rates. In Canada, a projected 30% of persons in correctional facilities are infected with HCV (41,42). As a result of previous life situations, a lack of harm reduction programs in correctional facilities, ongoing sexual violence, and unsafe tattooing and piercing practices, elimination of HCV in the prison system remains an ongoing challenge because primary prevention is often lacking. However, in June 2018, two federal prisons in Canada began trial needle and syringe programs (43), a long-overdue harm reduction strategy.

Screening within facilities in Canada is challenging and not universal. Some facilities test all new individuals on arrival; others have opted to require persons to ask for testing. Other barriers to getting tested include real or perceived lack of confidentiality with respect to medical records and the lack of access to treatment even if one is diagnosed. Although federal prisons in Canada have rolled out treatment programs (44), provincial systems typically do not initiate therapy (42), and Canada lags behind other comparable countries. Efforts to increase screening strategies in the United States and Europe have included frequent opt-in testing by venipuncture or DBS (reviewed in [45]), yet neither point-of-care nor DBS has been widely used in correctional facilities in Canada.

The Hep-CORE study evaluated testing and treatment in 25 European countries. Screening occurred in 84% of facilities in 16 countries, and it was reported that individuals had to specifically ask to be tested (46). Of these 25 countries, individuals in 21 had access to treatment in the facility, and only 5 had universal treatment irrespective of location and type of facility (46). Near-elimination campaigns have also been successful, with SVR rates in the high 90s. However, in one particular Australian study more than half of clients initially enrolled were released, transferred, or lost to follow-up, demonstrating the need for inter-facility coordinated care and community organizations to follow up with individuals who are released (47).

OST settings and dispensing pharmacies

One of the most well-described models of harm reduction and HCV treatment is the direct linkage to care for individuals who are receiving OST (reviewed in [19]). However, many of the models described were evaluated before all-oral DAA therapy. Nonetheless, few differences have been demonstrated in clinical trials in which individuals were subcategorized as receiving OST with treatment completion and SVR rates of 90% or more (26,48), and individualized models of care using DAAs have also demonstrated high SVR (49). Yet, no non-specialist-driven studies have evaluated engagement, linkage to care, and cure in OST settings.

Clients prescribed OST often receive directly observed therapy daily, multiple days per week, or weekly. As a result, pharmacy team members have frequent direct contact with individuals with past or current HCV risk factors and can initiate screening through mechanisms such as point-of-care antibody and RNA or testing by DBS (50,51). Pharmacists can also facilitate clients filling their prescription and initiating DAAs. In a study of 388 clients who were prescribed a DAA, median time to initiate treatment when community pharmacists were involved was 4 days. In this study, pharmacists also assessed for drug–drug interactions, facilitated reimbursement, provided reminder calls to clients, and assessed weekly for adverse events (52). At present, the largest pharmacy-led initiative, the SuperDOT-C study, has recruited more than 150 clients who have been randomly assigned to traditional care pathways or pharmacy-led services in 55 pharmacies in Scotland (53). If this model is successful, Canada may be able to adopt and modify it to incorporate on-site treaters because Canadian pharmacists, especially considering the very recent announcement that pharmacists in one province (and perhaps more in the future) can prescribe DAA therapy.

Nurse- and nurse practitioner–led initiatives to increase access

Nurses and NPs are members of multidisciplinary community HCV treatment programs, as described earlier, and fill important gaps in linkage to care and treatment. A salient example of this is Project ITTREAT, a “one-stop” nurse-led HCV screening and treatment program in substance misuse service in the United Kingdom, established as the result of difficulty engaging PWID. Recent data from this group reported 87% SVR among those who initiated therapy (54). A similar nurse-led model in Australia demonstrated that when PWID are first engaged by nursing in the community, they are more likely to accept health promotion (e.g., receive vaccinations and discuss harm reduction), work-up, and treatment (55). However, in both of these initiatives, infectious disease physicians, gastroenterologists, or hepatologists continued to be involved in treatment (54,55), perhaps limiting widespread implementation of such models.

One difficulty in adopting NP-led models of HCV care from other countries is the vast differences in scope of practice. In the United Kingdom, the NP role is defined by the sub-specialty courses completed, and much of the prescribing is protocol based, whereas in Australia NPs only make up 0.3% of nurses (56). Both of these factors may contribute to the lack of independent NP-led programs. In the context of HCV treatment in Canada, registered nurses, registered psychiatric nurses, and registered and licensed practical nurses were, and continue to be, an integral part of specialty and community HCV treatment programs, working with prescriber colleagues. NPs, however, are autonomous providers who practice independently and do not have limitations on prescribing ability in many provinces (DAAs or otherwise), similar to what is seen in the United States and the Netherlands (56). Thus, solo NPs who work in various settings serving those with HCV could and do treat on-site in conjunction with other medical care they are providing. Yet, to date NPs have not necessarily been well utilized in micro-elimination of HCV in Canada. This may at times be due to prescribing restrictions, but it is perhaps also related to a lack of understanding of the scope of NP practice by other clinicians, organizations, and government. In fact, to date there are no studies describing the number of NPs prescribing DAAs in Canada.

Despite these challenges, NP-led initiatives are an opportunity to increase access to screening and treatment in the geographical and organizational locations of those at risk of or with known HCV infection. In community settings in Canada, NPs have been shown to be more likely than GPs to work with individuals who are young, homeless, and female, as well as those without post-secondary education. Therefore, they may be ideally situated to reach HCV-positive individuals who have not been connected with care.

NPs have also been shown to spend more time in outreach settings and to more often be able to accommodate walk-in or drop-in visits (57). NPs and nurses provide holistic client-driven care in specialized and outreach services in which screening and treatment could take place as an adjunct to the services already being provided. These include rapid access to substitution therapy and home care, shelters, motels, overdose prevention settings, sexually transmitted infection and HIV pre-exposure prophylaxis clinics, and abused women’s centres, not to mention the many non-profit organizations that serve marginalized populations. Continued evidence to support these models, including drop-in testing and linkage to care, will better elucidate the number and types of individuals who are served through these models.

Key data gaps

In this article, we have highlighted that regardless of the mechanism of acquisition of HCV or situational circumstances, those initiating treatment have high SVR rates. However, although successes are described in terms of SVR, there is a paucity of literature describing types and teams of providers, program details, and successes and failures. We also acknowledge that we did not review Canadian or international literature on models of care for those who identify as Indigenous because Canadian literature is lacking, and we did not feel that literature from outside Canada would fully capture the contextual and structural circumstances of Canadian Indigenous persons. There is also a notable gap in the literature describing adolescent and youth engagement in testing and treatment, despite an increase in prevalence (58,59).

Finally, we appreciate that high SVR rates will not necessarily eliminate HCV. Although decreasing the number of infected persons within a closed facility or group who share similar transmission routes certainly decreases risk of acquisition, acknowledging factors that lead to reinfection such as exploitation and substance use, as well as underlying trauma and isolating circumstances, is critical. Moreover, although not covered in this article, peer programs and harm reduction workers who support individuals at risk of acquiring or infected with HCV promote an increase in screening, linkage to care, and the success of treatment programs (31,35,60–64).

Conclusion

Over the past few years, HCV treatment and access to medication in Canada has changed the rate at which those living with HCV can be cured. To fully operationalize these advances, treatment models of care must also change. Overall, the current body of evidence supports on-site services, which increase the possibility that individuals who test positive will initiate treatment (Figure 2). Striving to incorporate non-traditional models of care with less emphasis on specialist providers and working toward widespread engagement of community providers, agency staff, and peers is likely to increase testing, linkage, and cure.

Funding Statement

CanHepC is funded by a joint initiative of the Canadian Institutes of Health Research (NHC-142832) and the Public Health Agency of Canada.

Author Contributions:

Conceptualization, MJB and JJF; Writing – Original Draft, MJB and JJF; Writing – Review & Editing, MJB and JJF; Supervision, JJF; Funding Acquisition, JJF.

Funding:

CanHepC is funded by a joint initiative of the Canadian Institutes of Health Research (NHC-142832) and the Public Health Agency of Canada.

Disclosures:

Dr Feld discloses receiving honoraria for scientific consulting from AbbVie, Gilead Sciences, Merck, and Janssen. Dr Feld has received research support from AbbVie, Gilead Sciences, Merck, and Janssen. Dr Biondi discloses receiving honoraria for scientific consulting from AbbVie and Gilead Sciences and receiving salary for clinical and research support from Eve Medical and Specialty Rx Solutions.