People who use drugs are over-represented in the hepatitis C epidemic in Canada and globally. However, they are an underserved population when it comes to care and treatment because conventional treatment and care settings are not often designed to meet the needs of people who use drugs. Canada has signed onto the World Health Organization (WHO) targets to eliminate viral hepatitis by 2030, which include treating 80% of people with hepatitis C by that date.¹ To reach these targets, efforts must be made to prioritize the treatment of hepatitis C among people who use drugs, a recommendation also supported by the Blueprint to Inform Hepatitis C Elimination Efforts in Canada.²

Highly effective hepatitis C treatments, direct-acting antiretrovirals (DAAs), allow for a shorter treatment duration and have fewer side effects than the previously available interferon-based treatment. These new treatments have radically changed the hepatitis C treatment landscape, and coupled with expanded access to publicly funded medications, they introduce new programming possibilities. Integrating, or co-locating, treatment services into programs that are already serving people who use drugs, such as harm reduction programs, offers an opportunity to bring hepatitis C treatment to where people already feel comfortable accessing services and as a result to treat more people with hepatitis C.

This evidence review outlines findings related to integrating hepatitis C treatment services within harm reduction programs, focusing on the following topics:

• hepatitis C treatment adherence, completion and cure (known as sustained virological response [SVR]) rates within integrated hepatitis C and harm reduction programs
• acceptability of the integration of hepatitis C treatment services into harm reduction programs

What are the findings from this evidence review?

Most of the evidence in the literature looks at the integration of these services into opioid agonist therapy (OAT) programs. Limited evidence is available on integrating hepatitis C treatment services into needle and syringe programs or other types of harm reduction programs. The evidence can be summarized as follows:

• There is moderate evidence that integrating a hepatitis C treatment program within an OAT program results in high levels of treatment adherence, completion and SVR. In the studies that provided data, adherence ranged from 78% to 99%, treatment completion ranged from 96% to 97% and SVR rates (among treatment initiators) ranged from 79% to 94%. In studies that provided data, SVR rates among those who completed treatment ranged from 96% to 100%.
• There is limited evidence that integrating hepatitis C treatment services in OAT programs is accepted by both clients and providers.
• There is limited evidence that integrating hepatitis C treatment programs within needle and syringe programs and/or other types of harm reduction programs results in relatively high levels of treatment completion and SVR. In the two available studies, treatment completion ranged from 94% to 99%, and SVR rates ranged from 74% to 90% among treatment initiators and from 91% to 96% among those who completed treatment.

With the advent of DAAs, more research into the ways in which hepatitis C treatment services can be integrated into harm reduction programming is likely to emerge. This review does not seek to summarize the research information related to the effectiveness of DAAs in people who use drugs or who are on OAT, but rather looks at programmatic approaches to combining hepatitis C treatment and harm reduction program approaches (e.g., OAT, needle and syringe programs).

Further details of the methodology used for the literature review are available near the end of the article.

Hepatitis C in Canada and in people who use drugs

It is estimated that up to 246,000 people were living with chronic hepatitis C infection in 2011 in Canada and that 44% of people with chronic hepatitis C were unaware of their status.³ About one in four people clear hepatitis C on their own (spontaneous clearance). When someone doesn’t clear the virus within the first six months, they are considered to have a chronic hepatitis C infection, which can cause damage to the liver if left untreated.⁴ People with chronic hepatitis C infection need treatment with highly effective DAAs to be cured of hepatitis C.

In Canada, most hepatitis C infections are spread through the sharing of needles or other drug injection equipment (e.g., cookers, filters).⁵ In 2011, an estimated 66.0% of people who inject drugs and 28.5% of people who formerly injected drugs were antibody positive for hepatitis C.³ Globally, people who use drugs also have a high burden of hepatitis C incidence and prevalence.⁶

Canada signed on to the WHO’s global health sector strategy on viral hepatitis, 2016–2021, to eliminate viral hepatitis as a public health threat by 2030.⁷ The WHO strategy laid out national targets that include diagnosing 90% of people living with hepatitis C, treating 80% of people with hepatitis C who are eligible for treatment and reducing new infections by 90%.¹ To reach the targets set out in this strategy, approaches that specifically target prevention, testing and treatment of hepatitis C in people who use drugs need to be a priority. In addition, the Blueprint to Inform Hepatitis C Elimination Efforts in Canada (a document to guide action by policy-makers and program planners regarding hepatitis C elimination) recommends that elimination efforts among people who use drugs include moving care and treatment services to community-based environments. This includes places where people who use drugs are already accessing community-based services (e.g., harm reduction programs, community-based primary care).²

Hepatitis C treatment for people who use drugs

Treatment for hepatitis C is effective and cures over 95% of people within 8 or 12 weeks.⁴ DAAs have been approved for use in Canada since 2014.⁵ Fibrosis-related restrictions, which prevented some people from accessing treatment, were lifted across Canada by 2018⁸ and DAAs are now widely available, and publicly funded, across the country.

Although people who use drugs are over-represented in the hepatitis C epidemic, they are traditionally an underserved population when it comes to hepatitis C treatment⁹ and many access fewer primary health care services overall.¹⁰ This is despite the fact that research shows that hepatitis C treatment is highly effective and works as well among people who use drugs and those on OAT^11,12 as it does among the general population. According to treatment guidelines created by the Canadian Association for the Study of the Liver, all patients with chronic hepatitis C infection should be considered candidates for DAA therapy, and ongoing drug use by itself should not preclude hepatitis C care.¹³

Although guidelines recommend treatment for all people with chronic hepatitis C, barriers to accessing hepatitis C care and treatment exist for people who use drugs. Many of the barriers can be addressed through approaches such as integration, or co-location, of services within harm reduction programs (e.g., safer consumption sites, overdose prevention sites) or other programs/settings (e.g., HIV programs, primary care).¹⁴

Individual-level barriers to accessing hepatitis C treatment in people who use drugs are specific to each person. They can include:

• perceived stigmatization and mistrust of the health system^15–18
• the fact that people can have hepatitis C and be asymptomatic and unaware of their status¹⁷ or have a low perceived need for treatment¹⁸
• comorbid conditions (e.g., major depression, anxiety disorders)¹⁶
• poor engagement in care (e.g., missed appointments) due to multiple competing priorities ^15,17

Provider-level and systemic barriers include:

• lack of knowledge of the needs (e.g., health and social support needs) of people who use drugs^15,17
• reluctance to treat those who are actively using drugs, along with misconceptions regarding treatment effectiveness,^12,16,17,19 adherence and reinfection¹⁸
• lack of knowledge of hepatitis C testing and treatment among healthcare professionals, which can lead to the inability to adequately identify and treat people^15,17
• lack of appropriate treatment settings (e.g., lack of infrastructure for hepatitis C services) for people who use drugs^15,19,20

Integrating hepatitis C treatment into community settings for people who use drugs

The simplicity of new DAA treatment options allows for the diversification of treatment delivery away from specialists, primarily in hospital-based environments, to the delivery of treatment within community settings.¹⁹ Because of limited access to hepatitis C treatment by people who use drugs, integrating or co-locating treatment services into community settings that are already serving people who use drugs, could serve to increase treatment and cure rates.

Hepatitis C treatment services can be integrated, or co-located, in a variety of community settings to better reach people who use drugs, such as drug and alcohol treatment clinics, needle and syringe programs, supervised consumption sites and primary care.¹⁵ Other examples of locations where hepatitis C treatments could be integrated include community drop-in spaces or shelters – locations that meet people where they are. Integration can be accomplished through a variety of models, including nurse-led models, telemedicine models, multidisciplinary models, pharmacist-led models and models that use mobile van units to expand access to marginalized populations.¹⁹ Integration of services can also mean coordination of services between multiple sites to ensure the right mix of services are being provided.¹⁹ In addition to clinical providers, non-clinical providers such as care coordinators, social workers, drug and alcohol support workers and peer workers can also provide the necessary care and support.¹⁵

Integrating or co-locating services into a “one stop shop” can bring hepatitis C treatment services closer to where people are already accessing other health and social services. This approach can also simplify or eliminate steps required to access services. Several key elements of effective hepatitis C treatment approaches for people who use drugs have been identified, including*:

• use of support led by peers (i.e., people with lived experience of hepatitis C or drug use) for uptake and retention^10,19
• approaches that have flexibility to meet the needs of clients¹⁹ (e.g., drop-in hours for appointments)
• targeted efforts to test and treat those most affected by hepatitis C (e.g., people who use drugs)¹⁹
• strong referral links¹⁹ (e.g., peer navigation and accompaniment to appointments)
• efforts to re-engage people who use drugs who were diagnosed in the past¹⁹
• good patient follow-up and contact¹⁹ (e.g., being able to maintain contact with clients through tailored follow-up approaches)
• multidisciplinary programmatic approaches^15,19
• use of nurse-led care support for uptake and retention^10,19
• support for drug dependency, including harm reduction, social and psychological services in addition to medical care¹⁰

Integrating hepatitis C treatment into harm reduction programs

Harm reduction programs are often the first point of healthcare contact for people who use drugs, and they can reduce the stigma that people who use drugs may face in the traditional healthcare system. Harm reduction programs bring services to where people are and have the ability to adapt to the changing needs of people who use drugs, while continuing to engage people in care. In Canada and beyond, we must also acknowledge the reality of the current opioid crisis and the important role that harm reduction approaches play in managing this crisis, as well as ways to work toward addressing the holistic needs of people who use drugs.

The integration of hepatitis C treatment services within existing harm reduction programs can help to reach people who use drugs and who need hepatitis C treatment.^9,15,19

The following harm reduction programs are considered in this review for their potential integration with hepatitis C treatment services:

• Opioid agonist therapy (OAT), also called opioid substitution therapy (OST), can help people who want to reduce or eliminate their use of illicit opioids by helping to manage withdrawal symptoms and drug cravings. OAT medications are legal medications prescribed by a healthcare provider and they are considered first-line treatment for opioid dependency.
• Needle and syringe programs (NSPs) reduce the number of new HIV and hepatitis C infections by providing new equipment to smoke or inject drugs.
• Supervised consumption sites (SCS) and overdose prevention sites (OPS) have trained staff who supervise drug use to reduce the number of fatal overdoses. Sites may provide sterile drug use equipment for people to use pre-obtained drugs, thereby reducing HIV and hepatitis C infections.

These harm reduction programs and services can also connect people who use drugs to other needed health and social services.

OAT and hepatitis C treatment

Among the approaches to combining harm reduction programs and hepatitis C treatment, integrating OAT and treatment has been the most widely studied.²¹ Evidence on combining hepatitis C treatment with OAT programs began to be collected in the interferon era, as combining treatment with the dispensing of OAT medications was seen as an opportunity to support adherence to difficult interferon regimens. A variety of program models have combined the delivery of OAT with hepatitis C treatment (both DAAs and interferon), including speciality clinics with multidisciplinary teams and addiction specialists, community-based treatment using telemedicine, and treatment at OAT clinics.²² Although OAT programs have provided successful approaches to integrated care and may provide further opportunities with DAA therapy, it should be noted that OAT programs are not for everyone and people who use drugs may not want to participate in OAT programs, may not have had success with OAT programs in the past or may not have access to OAT programs.

Treatment adherence, completion and SVR

All of the programs considered below used DAAs for hepatitis C treatment, or a combination of interferon and DAAs (where noted). One randomized controlled trial (RCT) and six observational studies are included in this review. There is moderate evidence that integrating a hepatitis C treatment program within an OAT program results in high levels of treatment adherence, treatment completion and SVR. In the studies that provided data, adherence ranged from 78% to 99%, treatment completion ranged from 96% to 97% and SVR rates (among treatment initiators) ranged from 79% to 94%. In studies that provided data, SVR rates among those who completed treatment ranged from 96% to 100%.

An RCT in the United States (the PREVAIL study) recruited people who inject drugs and who have hepatitis C from an OAT clinic. Participants were randomly assigned to one of two intensive interventions, either modified directly observed therapy (mDOT) or group therapy, or to a control intervention, self-administered therapy for hepatitis C treatment.²³ When this trial started, interferon was the standard treatment, but the trial evolved to include DAAs as they became available (about one-quarter of participants were treated with interferon). One-hundred and fifty-eight patients were randomly assigned to treatment between October 2013 and April 2017, and 150 received the intervention as assigned. Interventions were as follows:^23,24

• Self-administered treatment: all medication was received from the clinic, packaged in seven-day blister packs and dispensed weekly, bi-weekly or monthly and self-administered at home.
• Modified directly observed therapy (mDOT): participants received mDOT during OAT visits (it was considered to be modified DOT as not all doses were observed). In cases where doses needed to be taken at home, participants received blister packs and were asked to return used blister packs at their next visit.
• Group treatment: an orientation/introductory meeting was held with six to 12 participants. Information on the risks and benefits of hepatitis C treatment (among other topics) was presented and psychosocial support, education and side effect management were discussed. Participants received interferon or a seven-day blister pack (DAAs) during group therapy.

The studies found the following results:²⁴

• Overall adherence was quite high at 78%. Adherence was highest in the mDOT arm (86%), followed by group therapy (80%) and self-administered therapy (75%). The difference in adherence between participants on mDOT and self-administered therapy was statistically significant; however, the difference was not statistically significant between those in group therapy and those in self-administered therapy.
• Treatment completion was very high at 97% among those who initiated treatment, with no statistically significant differences among groups.
• The overall SVR rate was very high at 94% among those who initiated treatment; SVR was highest in the mDOT arm (98%), followed by the group therapy (94%) and self-administered therapy arms (90%) (differences were not statistically significant). However, among those who received DAAs, SVR was 95% with no statistically significant difference between groups (100% mDOT, 95% group therapy and 90% self-administered therapy).

An observational study from the United States examined the feasibility of providing DAA treatment to people who use drugs in routine clinical care at an OAT program. The OAT program offered methadone or buprenorphine, intensive outpatient services, residential treatment and onsite psychiatric and primary care. Hepatitis C screening was offered to all of those who presented for OAT, and treatment was subsequently offered to those who tested positive for hepatitis C. Treatment data for 75 patients with hepatitis C who enrolled in the program between mid-2013 and mid-2015 were evaluated. Results indicate that:²⁵

• treatment adherence was very high at 99%
• the SVR rate was high: 85% among those who started treatment and 98% among those who completed treatment and follow-up

An observational study from Australia looked at a hepatitis C treatment and management program provided through a community-based agency that specializes in integrated harm reduction services (e.g., needle and syringe programs, drug and alcohol counselling). The program included case management, and worked with medical practitioners (e.g., nurses specializing in hepatology) and hepatology specialists (either on-site or external). Individuals were eligible to participate if they had hepatitis C and met any of the following criteria: current injection drug use, receiving OAT, receiving drug counselling or a community (i.e., outpatient) rehabilitation client. A few study participants were unable to access DAAs for this study because of lack of coverage and were treated with interferon-based treatments, but they were still included in the analysis. Results indicate that among the 127 participants:²⁶

• treatment adherence was very high at 92%
• treatment completion was very high at 96%
• the SVR rate was high: 80% among those who started treatment and 100% among those who completed treatment and follow-up

An observational study from Vancouver, Canada, looked at an interdisciplinary hepatitis C treatment program delivered by family physicians at a community-based primary care and addiction clinic. A family physician treated clients for hepatitis C, in addition to providing addiction services and OAT. The team included a hepatitis C focused nurse and counsellors, an infectious diseases consultant (by referral) and drop-in support groups. Clients were assessed by family physicians (e.g., hepatitis C history, liver assessment, substance use history) and decisions to initiate hepatitis C treatment were made by the interdisciplinary team and based on factors such as the client’s stability, the severity of their liver disease and their medical comorbidities. Before beginning treatment, clients were provided with education on adherence and reinfection. There were 253 participants enrolled in the study and 138 participants included in the analysis (many were excluded because they did not have SVR results before study publication). Participants were enrolled between October 2015 and October 2017. The Results indicate that:²⁷

• treatment completion was very high at 96%
• the SVR rate was high at 87% among those who completed treatment and even higher at 97% among those who completed treatment and follow-up SVR testing

An observational study from the United States looked at integrating a hepatitis C management program via telemedicine within an OAT program. Participants with hepatitis C were offered hepatitis C evaluation by telemedicine if they had been enrolled in an OAT program for at least three months. Consultations were performed by a hepatologist and an OAT program practitioner and consisted of a standard medical evaluation, a physical examination and the formulation of a treatment plan. DAAs were co-administered with methadone and “take-home” doses were provided for days when participants would be unable to attend the program. Bi-weekly telemedicine evaluations occurred with assessment of medication adherence and potential side effects. There were 62 participants in the study and 45 were prescribed DAAs. Results indicate that:²⁸

• adherence was quite high at 80% at week 2 and 90% at weeks 4, 6, and 8
• the SVR rate was very high at 93% among those who started treatment

An observational study from France conducted in 2014 included 50 participants with an active history of moderate to severe substance use disorder, or who were currently receiving OAT, or who met both criteria. Hepatitis C treatment was delivered in an addiction centre under the care of a multidisciplinary team (e.g., hepatologist trained in addiction care, educators). For those on OAT, DAAs were often provided at the same time as OAT on a weekly basis. Thirty-four patients (68%) were receiving OAT. Overall, 90% of participants who started treatment achieved SVR (two were lost to follow-up and three were not cured of hepatitis C).²⁹

An observational study from the United Kingdom looked at the use of a community-based nurse-led model for the screening, stratification and treatment of hepatitis C at an addiction service (i.e., Project ITTREAT). The program aimed to set up a “one-stop” hepatitis C community clinic that also provided hepatitis B vaccination, OAT and social and psychiatric support. The nurse was experienced in hepatitis C care and trained in addiction services. The program provided home delivery of hepatitis C medication (if required) and used peer advocates. The program took place from 2013 to 2017 and 485 participants were recruited. After assessment, 87 started treatment (both interferon-based and DAA regimens). Results indicate that:¹⁷

• treatment adherence was very high at 98%
• the SVR rate was somewhat high at 79% among those who started treatment, but among those who had an SVR result available, 87% achieved SVR

Acceptability

There is limited evidence from two observational studies that integrating hepatitis C treatment in OAT programs is accepted by both clients and providers.

An observational study from the United States looked at integrating a hepatitis C management program via telemedicine in an OAT program. Participants with hepatitis C were offered hepatitis C evaluation by telemedicine if they had been enrolled in an OAT program for at least three months. Consultations were performed by a hepatologist and an OAT program practitioner and consisted of a standard medical evaluation, a physical examination and the formulation of a treatment plan. DAAs were co-administered with methadone and “take-home” doses were provided when a patient did not attend the program in person. Bi-weekly telemedicine evaluations occurred with assessment of medication adherence and potential side effects.²⁸ Qualitative results found that participants were accepting of the program (demonstrated by their willingness to refer others) and that they appreciated the “one-stop shop” approach.³⁰

A qualitative study from Australia looked at the integration of hepatitis C treatment into an existing program that used pharmacy-based DOT for OAT. The study was completed between June and August 2017 and used semi-structured interviews with 12 people who injected drugs, who had lived experience with hepatitis C (current or past) and who were participating in OAT. OAT and hepatitis C treatment for this study were specifically in the context of pharmacies and some participants had yet to undergo hepatitis C treatment. Most of the participants who had undergone treatment (n = 9) stated that “overall treatment experience was straightforward and adherence wasn’t a challenge.” Participants (n = 8) explained that they perceived the approach of DOT for DAAs positively, and others (n = 4) explained that they had concerns about the idea. These participants indicated that adherence would not be an issue and some had concerns about being able to consistently attend pharmacies throughout their treatment. Participants valued the relationships that they had with the pharmacist who provided their OAT.³¹

Needle and syringe programs or other harm reduction program models and hepatitis C treatment

A 2018 international study surveyed safe consumption sites in 10 countries, including Canada, with respect to the provision of hepatitis C treatment. There were 49 valid responses to the survey. Fifty-four percent of respondents said they offered liver monitoring or disease management, and 21% said they offered hepatitis C treatment or were planning to offer it.³²

Despite the fact that hepatitis C treatment is being integrated into harm reduction programs, there is only limited evidence of high levels of hepatitis C treatment completion and SVR. In two observational studies, treatment completion ranged from 94% to 99%, and SVR rates (among treatment initiators) ranged from 74% to 90%. However, SVR rates ranged from 91% to 96% among those who completed treatment.

An observational study from the United States looked at outcomes when hepatitis C treatment services were co-located within a needle and syringe program. The project started in June 2014 and recruitment ended in December 2016. In the project, hepatitis C testing, medical evaluation, phlebotomy services, medication distribution, treatment adherence support and hepatitis C treatment services were co-located in a community-based needle and syringe program. Participants visited a drop-in centre for services and had flexible appointments. Participants determined medication dispensing (e.g., daily, weekly) and care coordinators provided ongoing support (e.g., adherence). The program had 80 participants, and 53 (66%) initiated treatment (43% were on OAT). Results indicate that:³³

• treatment completion was very high at 94%
• the SVR rate was very high at 90% among those who started treatment and 96% among those who finished.

An observational study that took place in Spain from January 2016 to July 2018 looked at people who use drugs who accessed hepatitis C treatment through a mobile harm reduction clinic. A multidisciplinary team cared for people who actively used drugs and offered needle and syringe exchange, OAT, addiction treatment, testing for infectious diseases, treatment for infectious, psychiatric and other diseases, counselling and social support. Services were offered seven days per week at two mobile locations. One hundred and sixty people started treatment through the mobile units and 86% were receiving OAT. Results indicate that: ³⁴

• treatment completion was very high at 99%
• the SVR rate was quite high at 74% among all people who started treatment; among people who finished treatment and follow-up, the SVR rate was 91%

What does this mean for service providers?

When developing programs, service providers should consider the key elements of effective hepatitis C treatment approaches for people who use drugs, which include:

• a “one-stop shop” approach to care provision that simplifies or eliminates unneeded steps or locations
• a multidisciplinary approach, which includes the use of models led by peers (i.e., people with lived experience of hepatitis C or drug use)
• flexibility in terms of appointments
• good follow-up and contact with clients for linkage and continued engagement in care.

Service providers should consider ways to integrate hepatitis C treatment services into harm reduction programs that are already being used by people who use drugs. Integrated services can serve people in locations that are easier for service users to access, more comfortable for them to use and more responsive to their health needs.

Available evidence indicates that treatment for hepatitis C in harm reduction programs can be highly effective in terms of hepatitis C treatment adherence, completion and cure. There is moderate evidence for integrating hepatitis C treatment and OAT programs, and limited evidence for integrating hepatitis C treatment and needle and syringe or other harm reduction programs. Although there is limited evidence on integrating hepatitis C treatment services into some harm reduction settings (e.g., needle and syringe programs) there is recognition that these integrated approaches could lead to better hepatitis C treatment coverage for people who use drugs.

With the introduction of new hepatitis C treatments, we will likely see increased approaches to the integration of treatment within program models that are serving people who use drugs. There are existing examples of hepatitis C treatment models being integrated into community-based and harm reduction programs in Canada, in both the interferon era and the DAA era. These treatment models provide comprehensive wraparound care and in some cases have done so for many years. The Calgary Urban Project Society (CUPS Calgary) program in Calgary and the Mobile Outreach Street Health (MOSH) program in Halifax provide integrated and multidisciplinary care, including the provision of mobile harm reduction and outreach services. A more recently developed program, the Hepatitis C Treatment Program at the Moss Park Consumption and Treatment Service in Toronto, provides hepatitis C treatment services within an overdose prevention site using a multidisciplinary and community-based model.

Methodology

The purpose of this literature review is to summarize research information on the treatment and acceptability outcomes associated with integrating hepatitis C treatment services into harm reduction programs. The search was completed in PubMed, Embase and Google Scholar. The key search terms used were: overdose prevention sites, safe, safer, supervised, consumption, injection, injecting, sites, rooms, facilities, needle, syringe, drug supply, exchange, distribution, opioid agonist therapy, opioid substitution therapy, drug substitution therapy, buprenorphine, methadone, harm reduction, hepatitis C, treatment and DAA. The MeSH terms used were: needle-exchange programs, opiate substitution treatment and hepatitis C/drug therapy. Searches were limited to research literature published between January 2015 and July 2019 (or the first 15 pages of Google searches limited to the past year) and were focused on North American or similar health systems (e.g., Australia, United Kingdom). Studies were included only if they focused on treatment with DAAs. Articles were also identified through the review of reference lists of relevant articles. Some articles that were published before 2015 were included in this review, if they were included in recently published literature reviews. Information on treatment with interferon was included if it was included in recently published systematic reviews or as part of a study that also considered treatment with DAAs.

Strength of evidence

The available scientific literature was reviewed to determine the treatment and acceptability outcomes associated with integrating hepatitis C treatment services into harm reduction programs. Although the evidence rating was flexible (to a certain degree), ratings were based on the following criteria:

1. Strong evidence: At least one systematic review or a large body of randomized controlled trials and quasi-experimental studies (with the support of observational research) supports the ability of the intervention to affect the outcome.
2. Moderate evidence: A limited number of randomized controlled trials and/or quasi-experimental studies (with the support of observational research) support the ability of the intervention to affect the outcome.
3. Limited evidence: Observational research supports the ability of the intervention to affect the outcome.
4. No evidence: No published research exists to support the ability of the intervention to affect the outcome.

The strength of the evidence is based on the quantity and quality of the evidence and not the size of the outcome.

* Note that this is based on research from both during and after the interferon era.

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