Hepatitis C Management Simplification From Test to Cure: A Framework for Primary Care Providers

Abstract

This article proposes a strategy for primary care providers to begin treating patients with hepatitis C virus (HCV). We are motivated by the need to expand HCV treatment and by developments that have simplified treatment for most patients. This article presents 5 steps to achieving quality HCV treatment in the primary care setting: (1) accurate diagnosis via reflex testing; (2) risk stratification and identifying comorbidities via pretreatment evaluation; (3) simple, once-daily, pan-genotypic HCV treatment regimens; (4) minimized on-treatment monitoring: and (5) posttreatment monitoring and high-quality care for comorbidities such as cirrhosis and injection drug use. We provide indications for referral to specialists: notably children, patients with genotype 3 and cirrhosis, advanced liver or kidney disease, previous treatment failures, drug interactions with recommended regimens, and hepatitis B co-infection. Finally, potential barriers for providers are discussed, as well as further research findings and policy interventions that can promote HCV treatment in the primary care setting. We believe that a substantial portion of patients with HCV can be treated safely and effectively by nonspecialists and that the engagement of primary care providers is critical to efforts to end the HCV epidemic.

INTRODUCTION

Hepatitis C virus (HCV) affects up to 5 million people in the United States and is a leading cause of liver disease and related mortality.^1–3 The HCV epidemic has been largely concentrated among the baby boomer generation, who account for most of the prevalent disease.^4,5 New cases are increasingly found in people who inject drugs, a risk pool that is growing because of the rising opioid epidemic.^6,7 Fortunately, treatment of HCV has evolved rapidly. New treatment regimens consisting of pan-genotypic direct-acting antiviral drugs have allowed most patients to be treated with all-oral, well-tolerated, short duration, and highly curative therapy.⁸

Effective treatment has sparked optimism that elimination of HCV is an achievable goal. Major biomedical societies, including the National Academies of Medicine, the Centers for Disease Control and Prevention, and the World Health Organization, have each outlined strategies for defining and achieving HCV elimination.^9–11 In each of these reports, supported by data from modeling studies, reducing mortality from HCV by expanding treatment is a key goal.¹² Because curing an individual of HCV is likely to prevent further HCV transmission, each report also cites the importance of treatment as prevention. Thus, there is a dual importance to scaling up HCV treatment: the individual health of the patient by preventing liver disease complications, and the health of the population by preventing new infection.

The delivery of HCV care is often visualized by using the cascade of care model. In this model, each step in the HCV diagnosis and treatment represents a target for intervention, with the goal of diagnosis and treatment of most HCV-infected individuals. There are large drop-offs in moving patients through the cascade, notably in confirming HCV diagnosis, linking patients to care, and initiating them on treatment.¹³

One potential reason for these drop-offs is that the availability of providers offering HCV treatment may be limited or difficult to access. This scenario has been shown to be the case particularly in rural settings^14,15 and for people who inject drugs.^16–18 Increasing treatment by primary care providers or substance use treatment providers without specialist referral is one way to promote treatment access. By increasing the pool of providers trained in treating HCV across diverse geographic regions and populations, we can reduce the number of drop-offs at each step in the cascade of care and move toward the goal of HCV elimination.

There are likely to be several barriers for primary care providers to begin treating HCV. Stigma associated with injection drug use behavior may prevent some providers from offering treatment.¹⁴ The administrative complexity of prior authorization and insurer restrictions on who can prescribe treatment may also be a barrier.^19,20 Even if primary care providers are willing to offer HCV treatment and practice in an environment in which insurer policies allow this treatment, they may not feel comfortable prescribing/administering new treatment regimens.

The present article proposes a simplified HCV management strategy that primary care or other non-HCV specialist providers can use to guide treatment of HCV-infected patients. A streamlined pretreatment evaluation, the use of pan-genotypic regimens, limited medical monitoring while on treatment, and quality posttreatment care for liver disease and substance use disorders are all highlighted. Also discussed are potential pitfalls and indications for referral of complex patients to specialty care. Potential administrative and financial barriers that must be resolved, as well as further research needed to support simplified treatment, are reviewed. Our objective is to offer information that will provide an instructional framework for primary care providers who wish to begin treating patients with HCV in their own practices.

PROPOSED FRAMEWORK FOR SIMPLIFIED MANAGEMENT OF HCV INFECTIONT

The figure shows the 5 steps that comprise the proposed framework. The following is a discussion of each step in more detail.

Figure.

The 5 steps of the proposed framework for simplification of hepatitis C management. Ab = antibody; HCV = hepatitis C virus; PCR = polymerase chain reaction.

Reflex HCV RNA Testing

HCV screening is currently recommended by national societies for “baby boomers,” born between 1945 and 1965, as well as for individuals with risk of HCV acquisition.^21,22 Based on current epidemiology, some experts have called for expansion of screening to all adults, and others for expanding testing to adolescents as well.^23–25 HCV screening is typically performed with an HCV antibody test, but this is not sufficient to establish a diagnosis.

Individuals with a positive HCV antibody test result need confirmation of active HCV replication with an HCV RNA polymerase chain reaction (PCR) test. Reasons for positive HCV antibodies and negative HCV RNA PCRs include spontaneous clearance, previous HCV treatment, and false-positive antibody test results.^21,22 Evidence from multiple settings indicates that many individuals with a positive HCV antibody test result do not get a subsequent RNA PCR confirmatory test.^23–25 Reflex HCV RNA testing, in which a positive serum HCV antibody is automatically sent for HCV RNA testing, has been shown to have equivalent test characteristics.²⁶ The Centers for Disease Control and Prevention now supports reflex testing as part of the recommended testing algorithm.²⁷ Reflex testing is already offered by most commercial laboratories. Ordering reflex testing as the standard of care eliminates the need for a second blood draw for HCV diagnosis and therefore may simplify evaluation and improve linkage to care.

Simplified Pretreatment Evaluation

The current guidance-based recommendations for testing before starting HCV treatment are summarized in Table I. Most of this evaluation can be conducted at a single laboratory visit. Specific considerations for pretreatment testing are as follows.

Table I.

Simplified pretreatment laboratory testing.

Test	Reason
Complete blood count	Low platelets may indicate cirrhosis
	Needed for APRI or FIB-4 calculation
Basic metabolic panel	Sofosbuvir/velpatasvir not indicated if eGFR <30 mL/min/1.73 m2
	If eGFR <30 mL/min/1.73 m2, may consider renal transplant evaluation before treatment (see Table II)
Hepatic function panel	Low albumin or elevated bilirubin levels may indicate cirrhosis or decompensated liver disease
	Needed for APRI or FIB-4 calculation
INR	Elevated INR may indicate cirrhosis or decompensated liver disease
HCV RNA	Perform if it was not done as reflex testing for HCV antibody positive
	Only patients with quantifiable HCV RNA require treatment
	Used to assess treatment response
HCV genotype	Recommend genotype 3 patients with cirrhosis be referred to HCV treatment specialist (see Table II)
Noninvasive tests for hepatic fibrosis*	Use in addition to APRI or FIB-4 for fibrosis staging when testing of liver elastography is unavailable

APRI = aspartate transaminase-to-platelet ratio index; FIB-4 = fibrosis index based on four factors; eGFR = estimated glomerular filtration rate; HCV= hepatitis C virus; INR= international normalized ratio.

^*Examples include FibroSURE (Laboratory Corporation of America, Burlington, North Carolina) and FIBROSpect II (Prometheus Laboratories Inc, San Diego, California).

Staging of Liver Fibrosis

The assessment of liver fibrosis is critical in the management of HCV-infected patients so that advanced fibrosis and cirrhosis are diagnosed and appropriately managed. The degree of hepatic fibrosis is often reported by using the METAVIR (https://www.ncbi.nlm.nih.gov/pubmed/8690394/) or Ishak (https://www.ncbi.nlm.nih.gov/pubmed/7560864/) fibrosis scores. Although the scoring systems differ slightly, scores of “F3” or higher are indicative of advanced fibrosis or cirrhosis. In contrast to earlier eras, in which liver biopsies were frequently needed to assess the degree of fibrosis, several validated noninvasive measures of liver fibrosis are now available that can be used to risk-stratify patients.

Two such measures, the aspartate transaminase-to-platelet ratio index (APRI) and the fibrosis index based on 4 factors (FIB-4), can both be calculated by using routine laboratory tests and clinical data. When possible, additional testing with either vibration-controlled transient elastography or serum measurements of direct biomarkers of liver injury should also be performed to improve the sensitivity of fibrosis detection. For the APRI and FIB-4, published scoring algorithms indicate the likelihood of advanced fibrosis or cirrhosis. For transient elastography and direct serum biomarkers, the results are interpreted and reported as a fibrosis score. In rare cases (eg, when scores are discordant or borderline), referral for liver biopsy may still be needed.

For patients with advanced fibrosis (eg, fibrosis METAVIR stage 3 equivalent) or cirrhosis, ultrasound examination is recommended every 6 months to evaluate for hepatocellular carcinoma. Patients with cirrhosis should also be referred for endoscopy to evaluate for esophageal varices. Patients with jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy have decompensated cirrhosis and should be referred to hepatology/liver transplant for managment⁸ (Table II).

Table II.

Indications for referral related to management of hepatitis C virus (HCV).

Indication for Referral	Type of Specialist	Reason
Indications for referral for specialist treatment of HCV
HCV genotype 3 and cirrhosis	HCV treatment specialist*	Resistance testing and/or ribavirin use may be required
Children	HCV treatment specialist*	Pan-genotypic regimens discussed are not yet approved for children
Hepatitis B surface antigen positive	HBV treatment specialist*	Hepatitis B treatment or monitoring may be required
Previous treatment failure	HCV treatment specialist*	Prior treatment failure may have led to drug resistance, requiring alternative regimens
Decompensated liver disease	Hepatology/liver transplant specialist	Need advanced management of liver disease, consideration for liver transplant.
		Some providers may want to refer all cirrhosis
HCC	Hepatology/liver transplant specialist	HCV treatment needs to be coordinated with HCC management
eGFR <30 mL/min/1.73 m2 or end-stage renal disease	HCV treatment specialist*	HCV treatment may need to be coordinated with renal transplant
Drug interactions with pangenotypic regimens	HCV treatment specialist*	May need alternative regimens or modification of other medications
Indications for specialist referral before or simultaneous with HCV treatment
Discordant results when staging fibrosis	Gastroenterology or hepatology specialist	Additional testing (sometimes liver biopsy) may be required to evaluate for cirrhosis
Cirrhosis	Gastroenterology or hepatology specialist	Endoscopy to evaluate for varices. Cirrhosis management if not being provided by primary provider
Untreated HIV co-infection	HIV treatment specialist†	Need to engage in high-quality HIV care along with HCV treatment
Current injection drug use or alcohol use disorder	Substance use treatment†	Referral to substance use treatment should be offered but does not need to be initiated before starting HCV treatment

eGFR = estimated glomerular filtration rate; HCC = hepatocellular cancer.

^*Hepatitis B virus (HBV) and HCV treatment specialist may be infectious diseases, gastroenterologist, or hepatologist depending on local expertise.

^†HIV and injection drug use can also be managed in primary care settings where resources and expertise exist.

Genotype Testing

Current guidelines recommend HCV genotype testing before starting therapy. However, with the advent of pan-genotypic regimens, the initiation of HCV treatment rarely varies according to the genotype. Clinical trial data, summarized in the next section, suggest similar efficacy across genotypes for both pan-genotypic agents currently on the market. Pan-genotypic regimens are recommended as first-line treatment for treatment-naive patients of all genotypes and subtypes.⁸ Regimen duration using the pan-genotypic regimens is also independent of genotype and depends only on staging of fibrosis. For now, pretreatment genotyping should still be performed, primarily so that patients with HCV genotype 3 infection who may require additional testing can be identified.

Not Recommended: Baseline Resistance Testing

Treatment guidelines currently recommend resistance testing only in select settings. Current resistance testing evaluates for resistance-associated substitutions (RAS), which are polymorphisms in the viral genome. The most important of these are in the NS5A gene, which encodes the drug target of many HCV treatment regimens. The impact of individual substitutions varies according to genotype and drug choice. For treatment-naive patients being considered for pan-genotypic regimens, the only situation in which resistance testing is currently recommended is for patients with cirrhosis and HCV genotype 3 infection who are being started on sofosbuvir/velpatasvir. This topic is discussed further in the next section, but given the relative rarity of this situation, we recommend specialist referral for patients with genotype 3 infection and cirrhosis. Because these patients will be referred, baseline resistance testing is not included in our proposed treatment framework.

Indications for Referral Before Treatment

Although many patients with HCV can likely be treated in primary care or nonspecialist settings, certain co-occurring conditions likely warrant referral to a specialist. Indications for referral and reasons are listed in Table II.

Treatment With Pan-genotypic Regimens

Current national guidelines recommend 4 possible drug regimens for the initial treatment of HCV, with possible inclusion of ribavirin or extension of treatment depending on host and viral factors.⁸ Although not compared head-to-head, all 4 showed high response rates and minimal toxicity. Thus, all options that offer high efficacy, favorable tolerability, and similar treatment duration are included as “recommended.” Guidance on regimen choice considers HCV genotype, baseline HCV RASs, cirrhosis status, and certain other host factors.

The end point of HCV treatment for most patients is cure. Cure is conventionally defined as sustained virologic response at 12 weeks (SVR12), which is when HCV RNA is not detected 12 weeks after treatment. This outcome has been associated with long-term suppression of HCV and improvement in clinical outcomes related to HCV.^28,29

To reduce the complexity of decision-making for providers, we have limited our initial treatment algorithm to the inclusion of the 2 pan-genotypic regimens currently available for HCV treatment: sofosbuvir/velpatasvir^* and glecaprevir/pibrentasvir^† (listed in order of US Food and Drug Administration [FDA] approval). The use of each in the initial treatment of HCV is discussed briefly to familiarize providers and to illustrate why these regimens were chosen for the proposed framework. We also highlight clinical trial data for the treatment of HCV genotype 3 infection that support our recommendation for specialist referral of patients with cirrhosis and genotype 3 infection.

Sofosbuvir/Velpatasvir

Sofosbuvir 400 mg/velpatasvir 100 mg (SOF/VEL) coformulates a nucleotide analogue NS5B polymerase inhibitor with an NS5A inhibitor into a single tablet given once daily with or without food for 12 weeks.³⁰ It is approved for use in adult patients with HCV genotypes 1 through 6. In addition to being pan-genotypic, advantages of SOF/VEL include lack of requirement for resistance testing in most circumstances (with a possible exception for genotype 3 [discussed later]), excellent tolerability, and sofosbuvir’s high barrier to resistance. In the large registration trial ASTRAL-1, a total of 624 direct-acting antiviral–naive participants with HCV genotypes 1, 2, 4, 5, and 6 (including 19% with compensated cirrhosis) received 12 weeks of SOF/VEL treatment. The result was an overall SVR rate of 99%,independent of genotype or baseline RASs.³¹ Separate studies enrolling patients infected with HCV genotypes 2 and 3 reported SVR rates of 99% and 95%, respectively, in participants receiving SOF/VEL.³² Some limitations of the regimen include the recommendation against using sofosbuvir in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² or end-stage renal disease, as well as some important drug–drug interactions.³⁰ Acid-reducing drugs such as proton pump inhibitors lower absorption of velpatasvir and may require discontinuation or dose adjustment before treatment. Medications that are inducers of P-glycoprotein or moderate to potent inducers of cytochrome P450 may reduce the plasma concentrations of SOF/VEL and should be avoided. Side effects are infrequent; when they do occur, they most commonly include mild severity headache, fatigue, nausea, and insomnia.

Another limitation of SOF/VEL relates to the effect of cirrhosis and RASs on SVR12 rates for genotype 3 HCV infection. In the registration study ASTRAL-3, 9% (n = 25) of participants receiving SOF/VEL harbored HCV with a baseline Y93H substitution that confers NS5A resistance. In this study, an SVR rate of 84% with Y93H achieved SVR compared with 97% when no NS5A RASs were present.³² Thus, current national guidelines recommend testing for resistance in patients with HCV genotype 3 and cirrhosis and the addition of ribavirin to SOF/VEL in the presence of the Y93H substitution.⁸

Glecaprevir/Pibrentasvir

Glecaprevir 100 mg/pibrentasvir 40 mg (GLE/PIB) coformulates an NS3/4A protease inhibitor with an NS5A inhibitor dosed as 3 tablets once daily with food for a total daily dose of 300/120.³³ GLE/PIB is also pan-genotypic and approved for use in adults with HCV genotypes 1 through 6. For initial treatment, it is given for 8 weeks for patients without cirrhosis and for 12 weeks for patients with compensated cirrhosis. In several registration studies, the 8-week duration of GLE/PIB achieved SVR in 98% to 99% of participants without cirrhosis, whereas the 12-week duration achieved SVR in 99% of participants with cirrhosis.^34–36 Advantages include the ability to use GLE/PIB in patients with renal dysfunction or end-stage renal disease without adjusting the dosage. One important limitation due to safety is that glecaprevir (and all HCV protease inhibitors) are not recommended in patients with decompensated liver disease because of the potential for hepatotoxicity. Important drug interactions result from GLE/PIB’s inhibition of P-glycoprotein, breast cancer resistance protein, and organic anion transporting polypeptide (OATP) 1B1 or 1B3, which can result in increased levels of drugs metabolized by these pathways. Similarly, drugs that inhibit these pathways may increase the plasma concentrations of glecaprevir and/or pibrentasvir. Lastly, drugs that induce P-glycoprotein/cytochrome P450 3A may decrease GLE/PIB plasma concentrations. Although glecaprevir levels are decreased by proton pump inhibitors, proton pump inhibitor use did not affect response rates in the large Phase III trial, and no dose adjustment is recommended in the package insert.^33,36

Side effects with GLE/PIB are infrequent; when they occurred, they most commonly included mild severity headache, fatigue, and nausea. In terms of resistance, baseline NS5A RASs had no effect on genotypes 1, 2, 4, 5, and 6. Notably, the presence of Y93H alone did not seem to affect treatment response for the initial treatment of genotype 3 (16 of 16 with SVR). Another NS5A substitution, A30K, was present in 10% of participants (n = 18) with HCV genotype 3 and was associated with an SVR rate of 78% (14 of 18) in patients who received 8 weeks of GLE/PIB. Only 1 patient who received 12 weeks of GLE/PIB had cirrhosis and A30K present and that person achieved SVR.³⁷ Currently, resistance testing is not recommended for genotype 3 with GLE/PIB use; however, the implication of NS5A resistance in genotype 3 continues to be explored.

As shown in Table III, these 2 regimens can be used in a complementary manner to cover nearly all clinical situations that arise in the initial treatment of HCV such as cirrhosis, renal disease, and proton pump inhibitor use.

Table III.

Comparison of regimens proposed for simplification of hepatitis C virus (HCV) management.

Variable	Sofosbuvir/Vel patasvir	Glecaprevir/Pibrentasvir
Treatment duration: no cirrhosis	12 wk	8 wk
Treatment duration: cirrhosis	12 wk	12 wk
Pill total	1 pill daily	3 pills daily
Food restriction	With or without food	With food
Use in renal disease	eGFR >30 mL/min/1.73 m2	No eGFR or dialysis restriction
Common primary care medicines/supplements that should not be coadministered*	Proton pump inhibitors†	Ethinyl estradiol
	St.John’s wort	Atorvastatin
	Carbamazepine	Lovastatin
	Oxcarbazepine	Simvastatin
	Phenobarbital	St.John’s wort
	Phenytoin	Carbamazepine
	Rifampin	Phenobarbital
	Amiodarone	Phenytoin
		Rifampin
Common primary care medicine drug interactions that require dose adjustment or monitoring*	Antacids	Fluvastatin
	Digoxin	Pitavastatin
	Warfarin	Pravastatin
	Atorvastatin	Rosuvastatin
	Rosuvastatin	Digoxin
		Dabigatran
		Cyclosporine
Use in decompensated liver disease	Indicated (with ribavirin); refer patient to specialist	Contraindicated; refer patient to specialist

^*In addition to package inserts, suggested online resources for identifying and managing drug-drug interaction include: aidsetc.org/resource/hiv-and-hcv-drug-interactions-quick-guides-clinicians and https://www.hep-druginteractions.org/

^†Coadministration not recommended. If required, sofosbuvir/velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg.

Minimal On-treatment monitoring

The current recommended monitoring for patients undergoing treatment with pan-genotypic regimens is minimal. A complete blood count, hepatic function panel, and HCV RNA PCR should be performed at 4 weeks of therapy. If these values are normal, further testing can be deferred until after treatment completion. A marked increase in liver associated enzyme test results (either a 10-fold increase in alanine transaminase levels or a smaller increase along with symptoms of liver injury) should prompt discontinuation of therapy and specialist referral. A smaller increase (<10-fold, with no symptoms) can be monitored with repeat testing. If this scenario occurs, patients with previous exposure to hepatitis B virus (HBV) (ie, HBV core antibody positive) should also have an HBV DNA sample sent to evaluate for the possibility of HBV reactivation (e.g. development of detectable DNA levels). Detectable HCV RNA PCR while on 4 weeks of therapy should be managed with adherence counseling and retesting at 6 weeks. If this value is higher than the 4-week value, treatment should be discontinued, and specialist referral is recommended.

Posttreatment Testing and Quality Care

Although HCV is curable for most patients, its associated comorbidities and complications often need ongoing management. Patients with cirrhosis currently have suboptimal rates of posttreatment monitoring for complications such as hepatocellular carcinoma.^38,39 Patients with ongoing injection drug use behavior can benefit from linkage to harm reduction or treatment to prevent re-infection.⁴⁰ Because primary care providers are likely to have longitudinal patient follow-up, these providers may be an ideal group to encourage quality care after an HCV cure.

Confirmation of Cure

HCV RNA PCR to confirm SVR12 should be performed 12 weeks (or later) following completion of HCV therapy. If SVR12 is not achieved, patients should be referred for retreatment by an HCV specialist (Table II). If SVR12 is achieved, patients should be informed that they were cured, then scheduled for appropriate follow up for HCV testing and liver disease monitoring (as discussed in a later section). Patients should be advised that HCV antibodies will stay positive for life, and this finding is not indicative of ongoing infection.

Preventing and Testing for Reinfection in Groups at Risk

During and after HCV treatment, risk factors for HCV acquisition should be reassessed, and patients should be provided education and linked to harm reduction resources to help prevent reinfection. Patients who express interest in substance use treatment, including medication-assisted therapy, should be linked to an appropriate provider. Follow-up HCV RNA testing (rather than antibody testing) should be performed at least annually in patients with ongoing risk factors for reinfection or patients who develop abnormal liver-associated test results after treatment.⁸

Liver Disease Management

HCV infection should be considered a liver disease in addition to a viral infection. As such, liver disease management does not end with SVR. Abnormal liver test results posttreatment warrant further evaluation to rule out fatty liver or other liver conditions. Patients with cirrhosis continue to require screening for hepatocellular carcinoma and esophageal varices, as well as education on avoidance of alcohol and hepatotoxic medications. Currently, there is no consensus on the end point for hepatocellular carcinoma screening, and patients should be advised that lifetime screening is recommended. As indicated in Table II, we propose that all patients with decompensated liver disease or hepatocellular carcinoma be referred to hepatologists or liver transplant centers. In addition, we include cirrhosis as a consideration for referral for practitioners who cannot provide liver disease management. One possible approach would be for providers new to HCV care to refer all patients with cirrhosis to specialists while providing treatment for patients without cirrhosis as they develop confidence in their management of HCV and liver disease. Given the widespread prevalence of fatty liver disease and alcoholism, the liver disease management skills developed with HCV care could be applied to these other diseases encountered commonly in practice.

INTERVENTIONS AND RESEARCH NEEDED TO FURTHER PROMOTE SIMPLIFIED TREATMENTT

Elimination of HCV Genotype Testing

Although pan-genotypic regimens are proposed for use in this model, we did not eliminate HCV genotype testing primarily because of genotype 3 management. As discussed earlier, diminished response rates for genotype 3 remain a concern, particularly in the setting of cirrhosis or when NS5A RASs are present. The full significance of RAS in this population remains to be determined, and current recommendations rely on expert opinion and extrapolation from small subsets of participants in clinical trials. Although genotype 3 is considered among the most challenging to treat, approved and unapproved regimens exist for retreatment in the event that the initial treatment is unsuccessful. Moreover, genotype 3 represents a minority of HCV infection in the United States, and only ~10% to 15% of those are likely to have NS5A RAS. If additional favorable data emerge regarding the performance of SOF/VEL, GLE/PIB, and the retreatment regimens for HCV genotype 3, genotype testing could be eliminated from the algorithm. This theory is already being explored in the United States and resource-limited settings in which genotype testing is cost prohibitive (eg, AIDS Clinical Trials Group 5360 study).

Less importantly, baseline HCV genotype may also be useful in evaluating patients who have a positive HCV RNA PCR after HCV treatment to help determine whether the treatment was not effective (relapse) or the patient was re-infected with a new strain of HCV. Because treatment failure is an uncommon event, universal baseline genotype testing for the exclusive purpose of understanding rare treatment failures is not warranted. In most cases, practitioners can rely on clinical history (eg, risk factors) and timing of viral rebound (earlier suggests relapse) to determine the cause.

Simplification or Elimination of Prior Authorization Criteria

Prior authorization requirements can be a substantial barrier for primary care providers to begin initiating treatment. Early after the release of direct-acting antiviral agents, many state Medicaid programs initiated criteria to restrict treatment to patients with high disease severity and abstinence from substance use, as well as restrict prescribing to hepatologists, gastroenterologists, or infectious diseases providers.^41,42 Although Medicaid programs have started to change these criteria, not all have. Managed Medicaid plans, commercial insurance plans, and Medicare part D or supplemental plans may also have additional prior authorization steps that vary significantly.¹⁹ Collaborative strategies to improve the efficiency of prior authorization, such as utilizing specialty pharmacies or patient navigators, have shown success.^43–46 However, these resources may not be available in all jurisdictions, and financing may not be available for dedicated staff. Simplification or elimination of prior authorization criteria that restrict treatment are needed to enable treatment expansion into primary care at a larger scale.

Evaluation of Successful Models of Integrated Care

Direct treatment by primary care providers of HCV-infected patients has shown high rates of SVR12, both for the overall population and for people who use drugs.^47–49 This outcome is also true in care settings that are specifically dedicated to highly marginalized individuals, such as homeless adults or those with mental illness.^50–52 Treatment models for patients undergoing opioid substitution therapy, including individual treatment, directly observed therapy, and group treatment, have all been comparably effective.^53,54 Finally, emerging evidence supports integrating treatment into syringe services programs.⁵⁵ The resources needed to provide treatment have varied; social workers, nurses, pharmacists, and care coordinators may all play key roles. In addition, telementoring programs have been developed to help providers begin treating HCV, although this approach requires available public health resources and may not be accessible to all providers.¹³ Other delivery models may be effective for different practice types, and not all models are necessarily reported in the published literature. There is likely no one-size-fits-all model for integrating HCV treatment into primary care, and further research that details the implementation of such treatment, the resources required, and the potential impact on patients is required.

CONCLUSIONS

Primary care providers are an ideal group to lead the charge on providing high-quality treatment at the scale that is needed to end the HCV epidemic. Because of revolutionary simplification in treatment regimens and evaluation, we believe that effective HCV treatment by primary care providers is possible. The present article offers an approach that providers can use in risk-stratifying patients, initiating and monitoring treatment, offering quality care after treatment, and deciding which patients to refer. As providers gain familiarity, and eventually expertise, with HCV treatment, they can begin to treat more complex cases. Sadly, systemic barriers still exist for primary care providers who seek to start treating HCV. We believe that it is time for the health care system to remove those barriers and promote widespread access to HCV therapy for all patients.