Integrating Management of Hepatitis C Infection into Primary Care: the Key to Hepatitis C Elimination Efforts

Abstract

Elimination of hepatitis C virus (HCV), a leading cause of liver disease in the USA and globally, has been made possible with the advent of highly efficacious direct acting antivirals (DAAs). DAA regimens offer cure of HCV with 8–12 weeks of a well-tolerated once daily therapy. With increasingly straightforward diagnostic and treatment algorithms, HCV infection can be managed not only by specialists, but also by primary care providers. Engaging primary care providers greatly increases capacity to diagnose and treat chronic HCV and ultimately make HCV elimination a reality. However, barriers remain at each step in the HCV cascade of care from screening to evaluation and treatment. Since primary care is at the forefront of patient contact, it represents the ideal place to concentrate efforts to identify barriers and implement solutions to achieve universal HCV screening and increase curative treatment.

INTRODUCTION

In 2016, the World Health Organization (WHO) called for the elimination of viral hepatitis as a public health threat by 2030, with elimination defined as a 30% reduction in the incidence of new HCV infections and a 65% reduction in liver-related deaths due to chronic hepatitis C virus (HCV).¹ An estimated 71 million people are living with chronic HCV worldwide, with only ~15% aware of their diagnosis.^1–4 In the United States (U.S.), approximately 2.4 million people have chronic HCV, with an estimated 50% aware of their diagnosis, of whom only 59% have access to an HCV provider, and only 30% have been prescribed HCV treatment.^{5, 6} President Biden issued a proclamation in May 2021 that the U.S. should aim to achieve HCV elimination by 2030 and reaffirmed “our commitment to ensuring everyone knows their viral hepatitis status, has access to high quality care and treatment, and lives free from stigma and discrimination”.⁷

Elimination has become a realistic goal for several reasons. First, diagnosis can be achieved with simple, inexpensive, and highly accurate diagnostic tests. Second, modes of HCV transmission are well understood, allowing targeted screening and rescreening as well as prevention strategies to be implemented. Since March 2020, the U.S. Preventive Services Task Force (USPSTF) recommended one-time screening for all adults from 18 to 79 years of age, thereby simplifying screening algorithms.⁸ Third, and most importantly, highly effective, well-tolerated, and short-course direct-acting antivirals (DAAs) offer very high cure rates of chronic HCV infection (>95%).^{9, 10} Treatment with DAAs has been repeatedly demonstrated to be cost-effective, even in practices serving low-income patient populations.¹¹ Moreover, simplified algorithms allow primary care practices to become the site for both screening and treatment of HCV. Given these favorable conditions to eliminate HCV, this narrative review summarizes the barriers that primary care providers and administrators face to successfully complete the HCV care cascade, which includes screening, diagnosis, evaluation, and treatment. We propose practical opportunities to address these barriers with the goal of promoting greater capacity for HCV to be managed by primary care providers.

METHODS

A targeted literature search of databases including PubMed and Google Scholar was conducted through March 11, 2022. This is a narrative, rather than systematic review, and we did not formally define search terms. The team, made up of one board-certified hepatologist, two board-certified internal medicine physicians, and one internal medicine resident, collaboratively determined which resources to utilize. We cited individual randomized controlled trials, non-randomized interventional studies, observational studies, systematic reviews, narrative reviews, post presentations, and qualitative studies. Reference lists of included studies were also used to identify additional sources.

Barriers in the Quest to Eliminate HCV

A global snapshot on progress towards achieving the WHO’s elimination targets was provided by recent Markov modeling that used inputs on population characteristics and epidemiology including prevalence and incidence rates. Remarkably, only 9 of 45 “high income” countries are on track to achieve HCV elimination by 2030, and the U.S. was not among them.¹² In fact, based on current rates of diagnosis and treatment, the projected time to elimination of HCV in the U.S. extends well beyond 2050.¹³ Among initiatives needed to speed time to elimination, robust public health education and screening programs as well as liberalizing restrictions on HCV treatment have been highlighted.¹⁴ Moreover, a multi-disciplinary, multi-pronged strategy is needed to identify and address gaps in the HCV care continuum (Table 1).^{12, 15–17}

Table 1.

Examining the HCV Cascade of Care Through a Problem-Based Lens

Screening:		Linkage to care:		Treatment:
Barriers	Examples of solutions	Barriers	Examples of solutions	Barriers	Examples of solutions
Knowledge of guidelines	Short course learning (online or in-person), integrate into trainee education	Referral to specialist	Co-localize diagnosis and treatment in primary care	Financial burden	Focus policy changes to cover HCV treatment to prevent long-term liver disease, utilize generics to decrease costs
Patient not screened	Increase EMR-based reminders, increase education, utilize “opt-out” screening, utilize POC testing	Patient not interested in treatment	Increase public health awareness, educate in clinic and at health fairs	Difficulty in accessing treatment	Train non-specialists to treat HCV, decrease patient and provider restrictions for HCV treatment, decrease transportation needs, use of telemedicine platforms to access patients
Patients not getting confirmatory test (HCV viral load)	Reflex testing of antibody-positive results, EMR-based reminders	Patient ineligible for treatment per state guidelines	Advocacy to remove all HCV treatment restrictions	Gaps in treatment course or failure to complete course of treatment	Dispense full course of medication at onset of treatment, engagement of pharmacists as treatment partners, patient reminders
Patient not presenting to primary care setting	Take testing to populations most at risk for HCV and those who are unlikely to present to primary care provider			Loss to follow-up or missed appointments	Decrease amount of surveillance labs and office visits to reduce patient visit burden and cost

Barrier #1: Screening and Diagnosis

Screening initiates the HCV care continuum and requires that challenges on multiple levels be addressed: system, provider, and patient. In regard to health system–related barriers, the older USPSTF guidelines on HCV screening were risk-based or confined to a limited age group, which added an additional layer of complexity to screening efforts.¹⁸ It is also important to note that HCV screening is not a quality of care metric, so it has lower priority than other national screening interventions such as mammography and colon cancer screening tests.¹⁷ Practice-specific barriers include the need to implement low-burden HCV screening procedures with straightforward follow-up. Patient-related barriers such as limited health literacy about HCV and negative attitudes about the stigma of HCV infection need to be considered.¹⁹ Public buy-in is exceptionally important for HCV elimination to be realized, as it has large effect on whether people choose to be tested and undergo treatment if indicated.²⁰ Furthermore, many high-risk patient groups do not regularly access health care in order to receive screening.

To mitigate health system–related barriers, the revised recommendation by the USPSTF in 2020 for one-time HCV screening of adults aged 18 to 79 promises to simplify and destigmatize screening.⁸ As a Grade B USPSTF recommendation, most insurers will cover HCV screening tests, but uninsured patients will still bear the financial burden unless covered by other sources.²¹ Adding HCV screening as a quality of care metric would help encourage providers to increase HCV screening among their patients. Primary care clinics are the ideal place to target efforts to increase HCV screening because they are a common entry point for a healthcare system and are where preventative care typically occurs. To address physician practice-related barriers, electronic medical record (EMR) features such as an automated reminder or a pop-up window can promote provider-driven HCV screening, while automated messages to the patient’s portal can remind patient to present to the laboratory for ordered lab tests.^{17, 22–24} In addition, providers can utilize an “opt-out” method in their practices for universal screening of patients for HCV, with patients learning about screening with posters or other sources of information without lengthy discussion or specific consent.^25–27

HCV screening is performed by an antibody test (anti-HCV) and, if positive, followed by confirmatory HCV RNA testing to establish presence of infection. The HCV RNA test is critical to distinguish the 15–45% of persons who have cleared their HCV infection spontaneously and do not need treatment.¹³ Historically, many patients with a positive HCV antibody test failed to receive subsequent HCV RNA testing.^{28, 29} A reflex HCV RNA test performed on the same blood sample can save time and effort by eliminating the need for the patient to return for a second blood test, thus reducing the risk of patients never learning that they have chronic infection.^{13, 21, 30} Increasingly, laboratories are offering reflex testing for HCV RNA and advocacy with local laboratories to change their approach to include reflex testing is a worthwhile endeavor.

To promote screening in traditionally hard-to-reach populations, rapid point-of-care (POC) HCV antibody testing can increase rates of screening.^{13, 31, 32} A randomized control trial of 200 persons at a drug detoxification center reported those with POC testing were almost 2 times more likely to receive a diagnosis of HCV than those with testing ordered in a laboratory.³³ Studies have shown the POC testing via community pharmacies, mobile clinics, and on the street increases delivery of screening.^{30, 34, 35} Importantly, POC HCV RNA testing has recently come on the market though not yet widely commercially available, but would offer an immediate diagnosis of chronic HCV infection, simplifying this initial step in the care cascade.^{36, 37}

We underscore the importance of expanded diagnostics options and screening locations, as several higher-risk populations have especially low rates of accessing care in clinic settings, and need targeted approaches to diagnose HCV infection.²⁸ These groups, such as the undomiciled, people who inject drugs (PWID), and the incarcerated, do not traditionally present to the outpatient clinic or hospital for medical care.^{13, 16} Innovative solutions are required for persons who do not typically present to the outpatient clinic or hospital for medical care.^{13, 16} Many studies have shown that targeted HCV screening at opioid treatment programs, drug detoxification centers, and halfway houses increases HCV diagnosis rates, and co-localizing HCV treatment at these locations increases HCV treatment uptake and completion.^{33, 38, 39} Prisons have instituted opt-out HCV testing at intake.^40–42 Another option is POC testing at mobile clinics, shelters, and street medicine providers.^{32, 43–45} Immigrants who are unlikely to present to primary care clinics or hospitals due to associated financial costs or immigration status can be reached at community health care events or community centers.⁴⁶ Furthermore, integrating HCV screening and treatment into HIV/STD clinics efficiently leverages pre-existing clinical infrastructure to increase HCV diagnosis and linkage to care.⁴⁷

To address patient-related barriers, public education is necessary to increase willingness to be tested and receive treatment when needed.⁴⁸ A variety of initiatives have aimed to increase public awareness and understanding about HCV infection by addressing screening and the availability of highly effective, curative oral medication regimens that can reduce the risk of HCV-related morbidity and mortality.^{12, 15, 49} On a large scale, the Centers for Disease Control and Prevention (CDC) has designated May as Hepatitis Awareness month aiming to educate the public through a variety of media approaches about HCV infection and the opportunity for a cure.⁵⁰ Studies have identified psycho-emotional and social challenges that reflect poor knowledge and barriers to supportive care of patients who have been newly diagnosed with chronic HCV.⁵¹ Thus, patients with chronic HCV need to be offered educational resources that can be efficiently provided on a mobile app to address these issues.^{21, 52}

Barrier #2: Linkage to HCV Care

All patients infected with chronic HCV should be treated, provided they have life expectancy of at least a year.¹⁰ Thus, the next major step in the cascade of care is linkage to a provider who can evaluate the stage of disease and offer appropriate treatment. Studies have shown that treatment initiation for HCV is low, even in this current era of DAA therapy, but improving. A study in a health care system of 8407 patients with chronic HCV who were eligible for treatment reported that less than 10% of these patients initiated treatment within the study period of 2 years (2014–2015) and the median time to treatment initiation was 300 days,⁵³ whereas a single center examining the proportion of patients initiating treatment in 2019–2021 found >40% of patients were initiating treatment and time from diagnosis to treatment was 33 days on average.⁵⁴ Health system, provider, and patient issues contribute to the low rates of treatment (Table 1).

Systems barriers play a major role in low rates of HCV treatment. A U.S. study examined administrative claims for HCV treatment from 2014 to 2018 and found that among treatment-eligible patients, commercially insured patients (69%) were more likely to receive treatment than Medicaid patients (30%).⁵⁵ Medicaid restrictions in some states continue to create unnecessary barriers for patients to access DAA therapies.²⁰ For example, some states still limit HCV treatment only to patients with advanced fibrosis.^{56, 57} However, this appears to be improving. For example, all states had some sort of restriction on HCV treatment by fibrosis level in 2014, but only 10% still had such restrictions in 2020.⁵⁸ Similarly, all states had sobriety restrictions for HCV treatment eligibility in 2014, but through advocacy initiatives, 16 states have dropped restrictions on sobriety and 23 states only require screening and counseling regarding substance abuse concurrent with HCV treatment considerations.^{28, 58} Given evidence that these patients can still be treated successfully, these restrictions on sobriety are unjustified and prevent access to effective, curative treatment.^59–64

In the past, the requirement for HCV specialist care was a formidable obstacle due to system, provider, and patient-based barriers. Patients would not only need a referral to an HCV-treating provider, but would also have to bear the additional time, effort, insurance co-pays, and transportation costs to obtain access to such care.⁹ Therefore, changes in HCV treatment prescribing privileges have been crucial for expansion of HCV treatment access. Research has shown that, with the simplicity and relatively low side effects of DAA therapies, HCV treatment can assumed by primary care providers.^65–68 Further, co-locating HCV diagnosis testing and treatment appears to increase the likelihood of moving through the care cascade, in part due to decreasing patient-related barriers as mentioned above.^{30, 34, 39, 66, 69} Other patient barriers include low medical literacy and lack of confidence in treatment or concerns of treatment side effects, which are best addressed through education, and management of concurrent mental health disorders and substance use disorders, that are best addressed by co-localization care.⁵⁵

As of 2020, 29 states allow any prescriber to treat HCV while 20 states require HCV treatment by or in consultation with specialists and 3 states allow only specialists to treat HCV. However, despite relaxed regulations that allow non-specialists to treat HCV, there is an insufficient number of providers who are willing or able to prescribe HCV treatment.^{14, 20, 29, 30, 68} Surveys of U.S. medical workers have identified several major perceived barriers to primary care provider treatment of HCV: time commitment for educating themselves in HCV treatment algorithms as well as educating their patients in HCV screening and treatment when indicated as well as addressing insurance coverage and reimbursement for liver disease staging and DAA therapy, all complicated by limited clinical support.^70–72 Thus, to increase provider capacity for HCV care, short-course training is needed for primary care providers. Prior studies have shown this to be achievable.^{21, 22, 34, 67, 68, 73, 74} For example, a clinical trial in the Washington D.C. area found that patients treated by advanced practice providers or primary care providers given a short 3-hour training had similar treatment outcomes compared to specialists treating chronic HCV.⁶⁷ These findings underscore the point also demonstrated in several other studies: chronic HCV can be effectively treated by non-specialists.^{66, 71, 73–75}

To help providers who have not traditionally treated HCV gain more experience, tele-mentoring programs (i.e., Project ECHO® in the U.S.) can be utilized; these programs have been launched worldwide, in places such as Australia, Rwanda, and India.^{48, 69, 76–79} These tele-mentoring programs increase primary care provider capabilities and confidence in treating HCV, which leads to more patients being cured of HCV.⁷⁸ Moreover, primary care providers who are treating chronic HCV should have ready access to specialists for support in this expanded practice and offer a resource for HCV-infected patients with complex or decompensated liver disease.

Additional laboratory testing after the initial HCV diagnosis can identify those patients who are best managed by or in conjunction with specialists due to advanced liver disease or comorbidities such as hepatitis B or HIV.¹⁰ Testing for advanced liver disease can be done by primary care clinicians as fibrosis staging no longer involves liver biopsy and can be achieved non-invasively.⁸⁰ The AST to Platelet Ratio Index (APRI) and the Fibrosis-4 (FIB-4) scores, which are calculated from routine laboratory tests (AST, ALT, and platelets), offer useful tools to stage disease.^80–85 An APRI score <0.50 or a FIB-4 score < 1.45 supports a low likelihood of liver fibrosis or cirrhosis, while an APRI score > 1.5 or an FIB-4 score > 3.25 indicates a high risk of advanced fibrosis or cirrhosis.⁸⁵ Complementary non-invasive ways to assess liver disease stage include ultrasound-based measures of liver stiffness (transient or shear-wave elastography).⁸⁴

For patients who likely have cirrhosis, ECHO programs and remote specialist consultation can support primary care clinicians to manage many of these more complicated patients¹⁰ and are especially important for patients living in rural, underserved, higher-risk, or impoverished communities.^{30, 39, 69, 86} However, resources and compensation are limited for this shared care model where the primary care clinicians manage the patient with specialist “back-up”; additionally, treatment of patients who have comorbidities, such as substance use and mental health disorders, can add to the complexity of management.^{28, 29, 53, 87–89}

Barrier #3: Prescribing, Monitoring, and Completing HCV Treatment

Every patient with active HCV infection (positive HCV RNA) should be considered for treatment (Fig. 1).¹⁰ Yet, for primary care practices who prescribe HCV therapy intermittently, the complexities of navigating insurance requirements and authorizations can be daunting. Strategies to overcome these logistical challenges include having insurance-specific requirements at hand before prescribing, partnering with specialty pharmacies, and using simplified treatment algorithms (Table 2). Pre-treatment requirements have been simplified but differ by state and insurer. For example, HCV genotype was needed previously to inform drug choice and duration of treatment, but the newer, pan-genotypic DAA drugs do not require this testing in DAA-naïve patients. Unfortunately, some medical insurance plans still require HCV genotyping prior to authorizing DAA medications, creating an unnecessary and non-justifiable extra step in the cascade of care.^{87, 90–92} This approval process places additional burdens on a primary care practice, but awareness of pre-treatment requirements can reduce delays in authorization. Additionally, although DAAs are well tolerated, primary care clinicians need to check for drug interactions^{93, 94} and, as noted above, identify clinically complex patients who require specialist care. Interactions can be performed using University of Liverpool’s HEP Drug Interactions online resource.⁹⁵.

Figure 1.

Algorithm for HCV screening, diagnosis, and treatment. *APRI and FIB-4 score can be determined with https://www.mdcalc.com. If patient with cirrhosis, consider referral to specialist for treatment. †If patient has been treated for chronic HCV in the past with DAAs, consider consultation with a specialist prior to initiating patient on HCV treatment given concerns for DAA resistance. ‡Standard treatment duration for patients with simple HCV infection not complicated by decompensated cirrhosis or liver cancer.

Table 2.

Prescribing HCV Therapy in Primary Care: Challenges and Solutions

Specific elements of treatment	Potential strategies/solution in primary care
Pre-treatment requirements	• Insurers may have different requirements for pre-treatment laboratory tests or abstinence requirements. Staff can assist providers by obtaining these requirements as well as preferred DAA options from the insurance plan up-front. • Multidisciplinary teams that include psychiatry and addiction medicine may be needed given the presence of these comorbidities in patients with HCV. • Community health workers are an important resource for HCV treatment adherence for patients.
Preferred DAAs	• Insurers may have preferred DAA options and it saves considerable time and effort if the preferred drug is known, allowing selection of a drug that will not require additional justification. • Most insurers have narrowed their preferred drugs to one of the two pangenotypic regimens — sofosbuvir-velpatasvir and glecaprevir-pibrentasvir — so familiarization with these drugs is most important.
Insurance authorization	• Partnering with specialty pharmacies is an effective way to reduce the time that staff spend on the authorization process. • If the clinic has a pharmacist, these individuals are well suited to support the prescribing/authorization process. • Uninsured patients access drugs through patient assistance programs; knowledge of these programs and their requirements is important for primary care providers serving uninsured patients. • In some states (e.g., California), advocacy has led to removal of the requirement for pre-authorization, which has streamlined prescribing considerably.
Refills and need for on-treatment testing	• Treatment interruptions are important to avoid. Adherence support can be provided through telephone or telemedicine visits. • Most patients are given 4 weeks of drug at once. For those on glecaprevir-pibrentasvir (8-week treatment), only one refill is needed, whereas for sofosbuvir-velpatasvir, 2 refills are needed (12-week treatment). This may be a factor in DAA selection. Education patients to seek refills at least 1 week prior to anticipated date of need is important as additional authorizations may be needed. • Insurers may require HCV RNA testing on treatment. While this is no longer recommended by guidelines — it is important to know insurer-specific requirements for refills. • Specialty pharmacies provide excellent support for patients and ensure timely refills, providing additional rationale for partnering with these pharmacies if possible.

The Infectious Diseases Society of America and American Association for the Study of Liver Diseases advocates for a simplified approach to HCV treatment with no laboratory visits during treatment and one or two telehealth visits during treatment to support adherence; this approach has been shown to increase patient compliance with treatment and achieve high cure rates.^{10, 106} Community health workers may be important adjuvants to the care team. If resources allow, patient navigators increase patient linkage to care after initial diagnosis of chronic hepatitis C and partnering with specialty pharmacies is another means to streamline medication authorization and to provide patients support during treatment (Table 2).^107–111 Thus, primary care practices need to consider the best options for patient support during their journey from HCV diagnosis to cure, with the recognition that resources may be limited.

As highlighted, high rates of HCV cure are achievable with current all-oral DAA regimens (92–100%).^{53, 96–101} However, treatment failure does occur, oftentimes due to treatment non-adherence, which can be due to many factors including food insecurity, housing insecurity, financial insecurity, illicit drug use, and untreated mental health disorders.^{20, 102, 103} Studies have shown that addressing these psychosocial factors leads to improved medication compliance and increased HCV cure rates as indicated by sustained viral response (SVR) at 12 weeks post-treatment.^{39, 59, 88, 104, 105} Thus, appraising a patient’s readiness for treatment is important and consideration given to the additional clinic or community supports that could be leveraged to maximize adherence.^{111, 112} For more complex patients or those who have failed HCV treatment in the past, primary care providers would likely need specialists to guide decisions regarding retreatment.

Teaching Trainees to Treat Chronic HCV

Since HCV treatment has been dramatically simplified with pan-genotypic treatment regimens in recent years (Fig. 1), HCV should be included in trainee education. Training medical students or residents to utilize new practice guidelines is a useful strategy to substantially increase the number of HCV providers and to engage eager trainees in evidence-based medicine. Currently, few primary care providers, including those involved in resident education, are trained to treat HCV. Thus, the key to integrating HCV treatment into outpatient residency curricula will be providing HCV treatment training to supervising attending physicians in resident clinics so they are comfortable with teaching chronic HCV evaluation and management in their own practices. Two small single-center studies have demonstrated that a structured HCV education and treatment program can offer trainees valuable experience in treating HCV in a supervised setting.^{74, 113} Training the next generation of physicians to treat HCV in the primary care setting not only builds HCV management capacity, but also can expand treatment access to vulnerable populations that cannot typically access hepatologists for treatment.^{75, 114}

CONCLUSIONS

HCV elimination is possible, but only with the engagement of primary care providers, as it requires large-scale screening and treatment coupled with innovative outreach efforts to reach underserved populations. Advances in recent years make HCV infection a more straightforward condition to diagnose and treat. Few chronic diseases are curable; in contrast, HCV can be cured with as little as 8–12 weeks of treatment. To address barriers hampering HCV eradication, we must undertake universal HCV screening, including beyond the traditional clinic walls, increase primary care provider knowledge and confidence in HCV management, and advocate for removal of HCV treatment restrictions so that all patients with HCV can be cured. Actively campaigning for HCV health policy change, specifically by making HCV screening a quality-of-care metric and continuing to decrease prescriber restrictions for HCV treatment to broaden treatment capacity are key opportunities for improvement. Primary care providers stand at the forefront of the elimination agenda — with the capacity to more efficiently complete the cascade of care to achieve a cure. It is only with an expanded capacity for care provided by primary care providers that the U.S. has the potential to achievement of WHO elimination targets sooner than the currently projected date of 2050.

Author Contribution

Norah Terrault is the guarantor of the article and all authors approved the final version of the manuscript. The authors made the following contributions:

Concept and design: Wang, Terrault.

Initial drafting of the manuscript: Wang.

Critical revision of the manuscript for important intellectual content: all authors.

Declarations

Conflict of Interest

NT: Institutional grant support from Gilead Sciences, GSK, Helio Health and Roche-Genentech and consulting fees from Moderna. All other authors deny conflicts of interest.