Selection for liver transplantation

Clinical Liver Disease

Volume 2, Issue 4, pages 145–147, August 2013

Review

Adam Peyton D.O., Paul Martin M.D.^*

Article first published online: 19 AUG 2013

DOI: 10.1002/cld.218

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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Despite advances in the treatment of chronic liver disease (most notably viral hepatitis), cirrhosis remains the twelfth most frequent cause of death in the United States and results in 33,539 deaths annually.1 Only a fraction of the individuals with advanced liver disease benefit from liver transplantation (LT), with approximately 7000 recipients per annum. Although innovations such as living and split donor transplantation have modestly enhanced transplant rates, only a substantial increase in the deceased donor pool will increase transplant activity. Currently, 17,000 people await LT, with more than 1500 wait-listed patients dying annually. The Model for End-Stage Liver Disease (MELD) score, an objective method adopted in 2002 for organ allocation in the United States, has resulted in a reduction of deaths on the waiting list. Despite the continuing debate about its application in some circumstances [e.g., hepatocellular carcinoma (HCC)], the MELD score has stood the test of time as an equitable system for the distribution of a scarce resource.

Indications (Table 1)

The commonest indication for LT in adults is decompensated cirrhosis, which in turn reflects the most frequent etiologies of chronic liver disease (Fig. 1); these include chronic hepatitis C virus (HCV), alcohol, cholestatic disease, and fatty liver disease. Another prominent indication for LT is small, nonresectable HCC.

Figure 1. Indications for LT (2011 Organ Procurement and Transplantation Network data).

Table 1. Indications for LT

Chronic noncholestatic liver disorders

Chronic hepatitis B

Chronic HCV

Autoimmune hepatitis

Alcoholic liver disease

Cholestatic liver disorders

Primary biliary cirrhosis

Primary sclerosing cholangitis

Biliary atresia

Alagille syndrome

Nonsyndromatic paucity of intrahepatic bile ducts

Cystic fibrosis

Progressive familial intrahepatic cholestasis

Metabolic disorders causing cirrhosis

Alpha-1-antitrypsin deficiency

Wilson's disease

Nonalcoholic steatohepatitis and cryptogenic cirrhosis

Hereditary hemachromatosis

Tyrosinemia

Glycogen storage disease type IV

Neonatal hemochromatosis

Metabolic disorders causing severe extrahepatic morbidity

Amyloidosis

Hyperoxaluria

Urea cycle defects

Disorders of branch chain amino acids

Primary malignancies of the liver

HCC

Hepatoblastoma

Fibrolamellar HCC

Hemangioendothelioma

Fulminant hepatic failure (ALF)

Miscellaneous conditions

Budd-Chiari syndrome

Metastatic neuroendocrine tumors

Polycystic disease

Hepatopulmonary syndrome

Retransplantation

This table was adapted with permission from Hepatology.2 Copyright 2005, American Association for the Study of Liver Diseases.

Importantly, even though most adult LT recipients have cirrhosis in the absence of complications, its diagnosis does not imply a need for transplantation. Some simple clinical details, such as the presence of varices, ascites, infection, or renal failure, provide useful prognostic information for the patient with cirrhosis3 (Table 2). A referral for LT should be considered when a patient with cirrhosis experiences an index complication such as ascites, variceal hemorrhaging, or hepatic encephalopathy that cannot be managed medically or when the MELD score of a patient with declining hepatocellular function approaches 15 (Fig. 2). Importantly, a stable patient with cirrhosis can deteriorate quite precipitously once a major complication such as variceal hemorrhaging supervenes. However, acute decompensation in a previously stable patient with cirrhosis can often respond to prompt medical therapy, such as the control of variceal hemorrhaging via endoscopic banding with other measures, including antibiotic prophylaxis. Implicit in the decision to initiate an LT evaluation is an absence of effective medical therapy (e.g., corticosteroids for autoimmune hepatitis) or a reversible component in hepatic decompensation (e.g., continued alcohol use). Although LT is unequivocally beneficial for recipients with advanced liver disease, the introduction of the MELD score (http://optn.transplant.hrsa.gov/resources/MeldPeldCalculator.asp?index=98) has helped define which patients should undergo transplantation.4 Recipients undergoing LT with a MELD score less than 15 had significantly higher 1-year mortality in comparison with candidates with similar disease severity who remained on the waiting list. A transplant survival benefit was unequivocally observed at MELD scores of 18 and higher, with the magnitude progressively increasing with higher MELD scores5 (Fig. 3).

Figure 2. Chart for determining when to refer someone for an LT evaluation.

Figure 3. Comparison of mortality risks (expressed as hazard ratios) by MELD scores for LT recipients versus candidates on the LT waiting list. Reprinted with permission from American Journal of Transplantation.5 Copyright 2005, Blackwell Munksgaard.

Table 2. Stages of Cirrhosis

Stage of Cirrhosis	Criteria	Prognosis: Mortality/Year (%)
1	Compensated, no varices	1
2	Varices	3.4
3	Ascites	20
4	Gastrointestinal bleeding	57
5	Infections and renal failure	67

HCC has become a prominent indication for LT, and this reflects not only its rising incidence but also the enhanced priority for organ allocation for HCC within the Milan criteria. Currently, nearly 20% of adult transplants in the United States are performed for HCC. Nearly half of these (9.9% of the overall total) reflect the allocation of 22 MELD points for potential recipients within the Milan criteria (i.e., a single HCC ≤ 5 cm or up to three tumors, none > 3 cm, without vascular invasion, regional node involvement, or distant metastases).6 Continued areas of controversy include downsizing larger tumors with chemoembolization to fit these criteria because, in comparison with tumor size alone, tumor biology more accurately reflects the risk of HCC recurrence.7 A report from the University of California San Francisco suggested that recipients with a solitary HCC up to 6.5 cm or with up to three lesions, the largest of which was ≤4.5 cm with the sum of the diameters no larger than 8 cm, had outcomes similar to those of patients meeting the Milan criteria.8 However, expansion beyond the Milan criteria for extra MELD points has not been generally accepted, and this reflects continued uncertainty about the role of LT with a more extensive tumor burden.

Hepatopulmonary syndrome is another complication of cirrhosis that is potentially eligible for extra MELD points because LT can favorably alter its course. Potential recipients must have an arterial oxygen tension less than 60 mm Hg on room air without underlying lung disease to receive these points. However, patients with HPS who have an arterial oxygen tension less than 50 mm Hg alone or in conjunction with a preoperative shunt fraction greater than 20% were 7.5 times as likely to experience perioperative mortality.9 Portopulmonary hypertension is another important extrahepatic complication of cirrhosis. Potential recipients suffering from portopulmonary hypertension with a mean pulmonary artery pressure greater than 35 mm Hg despite vasodilator therapy are usually not candidates for transplantation because of the magnitude of the perioperative and postoperative risk of cardiopulmonary complications. Acute liver failure (ALF) is defined as severe liver injury with encephalopathy and coagulopathy [international normalized ratio (INR) > 1.5] in a patient without preexisting cirrhosis and with an illness of less than 26 weeks' duration. ALF has a variable prognosis depending on the etiology and the likelihood of spontaneous recovery. The acknowledgment of the rapidly progressive course of ALF and its high mortality rate has led to its prioritization for LT if specific criteria are met.

Abbreviations

ALF acute liver failure

HCC hepatocellular carcinoma

HCV hepatitis C virus

INR international normalized ratio

LT liver transplantation

MELD Model for End-Stage Liver Disease.

Evaluation Process

Key components of the evaluation for LT include an assessment by a transplant hepatologist and surgeon to confirm that the patient's liver disease is of such severity that LT is reasonable and feasible and that other therapeutic options have been exhausted. A comprehensive medical assessment is undertaken to exclude important comorbidities such as coronary artery disease (Table 3). Once these consultations and investigations are complete, the patient's candidacy is discussed at a formal patient selection meeting. If the patient is accepted and financial clearance is obtained, the patient can be listed to wait for a donor organ for transplantation.

Table 3. Contraindications to LT

Absolute contraindications

Brain death

Anatomical abnormality precluding LT

Acquired immune deficiency syndrome

Advanced cardiac or pulmonary disease

Ongoing alcohol/illicit drug use

Extensive thrombosis involving superior mesenteric vein and portal vein

Extrahepatic malignancy

ALF with intracranial pressure > 50 mm Hg or cerebral perfusion pressure < 40 mm Hg

Persistent noncompliance

Lack of psychosocial support

Uncontrolled sepsis

Relative contraindications

Advanced age

Severe malnutrition/debility

Morbid obesity

Human immunodeficiency virus

Multiorgan failure

Psychological instability

Cholangiocarcinoma

References

Source

MELD score, allocation, and distribution in the United States

Clinical Liver Disease

Volume 2, Issue 4, pages 148–151, August 2013

Review

Joel P. Wedd¹, Ann M. Harper², Scott W. Biggins^1,*

Article first published online: 19 AUG 2013

DOI: 10.1002/cld.233

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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There is a critical mismatch in liver transplant supply and demand (Fig. 1). In order to manage this scarce resource, the transplant community in the United States has used the Model for End-Stage Liver Disease (MELD) score as the backbone of its adult liver transplantation allocation and distribution system since February 2002. The MELD score was implemented in response to the Organ Procurement and Transplantation Network (OPTN) Final Rule, a Department of Health and Human Services mandate to de-emphasize waiting time and focus on disease severity and waiting list mortality risk.1 The MELD score uses objective parameters to estimate the short-term risk of death in patients who are on the transplant list. Compared with the previous system, which used the Child-Turcotte-Pugh score2 and patient location (i.e., outpatient, hospital floor, or intensive care unit) to prioritize liver allocation, the MELD-based system was thought to be far more difficult to manipulate and less dependent upon waiting times for organ allocation. There was immediate evidence of a positive impact of the MELD score implementation, with fewer listings of low MELD patients and shorter waiting time on the liver transplant list in the first year of the post-MELD era.3 Despite the listing of sicker patients, however, there was no reduction in posttransplantation patient or graft survival.4

Figure 1. Discrepancy between candidates on the liver transplant waiting list and liver transplants.

The MELD equation uses the international normalized ratio, creatinine, and total bilirubin to determine a score from 6 to 40 (capped by United Network for Organ Sharing) and predicts 3-month mortality risk5 (Fig. 2):

where INR is the international normalized ratio.

Figure 2. Three-month waiting list mortality risk by MELD score.

The objectivity and ease of laboratory measurement of its variables make the MELD score an attractive organ allocation tool. After listing, every patient is placed on the list based upon their calculated or exception MELD score, which is periodically updated while awaiting transplantation. Patients whose calculated MELD score is not reflective of their risk of death or who drop out from the transplant list can be considered for exception points. Some disease states (hepatocellular carcinoma, hepatopulmonary syndrome, primary hyperoxaluria, familial amyloid polyneuropathy, cystic fibrosis with progressive pulmonary deterioration, portopulmonary syndrome, and cholangiocarcinoma receiving an approved chemoradiation protocol) can receive standardized MELD exception points provided they fit within predetermined criteria. Other considerations (e.g., hyponatremia and frequent cholangitis in primary sclerosing cholangitis) do not qualify for standard MELD exception points but are reviewed by each region's review board. The justifications for MELD exception points for many of these conditions were reviewed by a national concensus conference (MELD Exception Study Group and Conference, MESSAGE), which agreed on guidelines that are not used by all regions or all regional reviewers.6

Liver Transplantation Allocation and Distribution

Prioritization on the transplant waiting list is ordered by increased risk of death as determined by the MELD score (either calculated or exception MELD score, whichever is highest) with the exception of status 1a patients (acute liver failure, primary graft dysfunction, or hepatic artery thrombosis within 1 week of transplantation) and status 1b patients (children with chronic liver disease and life-threatening complications), who are prioritized first. For more information on the current allocation system, please see the Organ Procurement and Transplantation Network (OPTN) website (policy 3.6).7 The United States liver organ distribution is organized into 58 federally approved Donation Service Areas, each served by an Organ Procurement Organization (Fig. 3). With the exception of status 1A and 1B candidates, local candidates are prioritized over regional and national candidates.8 The priority MELD score cutoff for nonlocal candidates receiving an adult deceased donor liver offer preferentially over a local candidate is under continual revision to provide the most equitable sharing between regions that have inherently different demographics and degrees of illness. Currently, the “Share 15 Regional” policy establishes that cutoff at a MELD score of 15. If there are no local candidates above a MELD score of 15, the liver is offered regionally to candidates with scores of 15 or higher. The MELD score of 15 was chosen because of a seminal study showing that the balance between the risk of death on the transplant list versus risk of death with transplant surgery reverses around a MELD score of 15, with scores lower than 15 favoring staying on the transplant list and higher scores favoring accepting the risk of the surgery.9

Figure 3. Organ Procurement Organization (OPO) donation service area map.

Despite its improvement over previous allocation systems, the MELD score's weaknesses are widely recognized and reported. All of the MELD variables are subject to one or more of the following biases: laboratory variation,10, 11inaccuracy due to surrogate measurement and differential effects between men and women,12 and lack of specificity to liver disease.13 These biases may cause changes in an individual patient's MELD score that are not reflective of the patient's liver disease and therefore inappropriately change that patient's MELD-determined transplant priority. Despite these inherent weaknesses, the MELD score has created an evidence-based gold standard to assess risk equivalency in end-stage liver disease.

Abbreviations

MELD Model for End-Stage Liver Disease

OPTN Organ Procurement and Transplantation Network.

Recent Changes and Future Directions

Conversations within the transplant community are currently taking place to determine the next steps in MELD score, allocation, and distribution. The goal is to improve liver transplant equitability in the United States without sacrificing the objectivity and accessibility of the MELD score. The stated strategy involves small, incremental changes over time. In terms of allocation, the leading consideration is the MELDNa score—an equation similar to the MELD score that incorporates sodium and has shown better predictive ability than the MELD score, especially in low MELD scores.14, 15 A proposal to incorporate the MELDNa score into the United States allocation system was submitted for public comment in Spring 2013. Efforts to refit the MELD score variables with new coefficients in cohorts larger than those of the original MELD studies have resulted in higher predictive ability, both with and without sodium in the score,16, 17 but this is currently not under consideration for implementation.

There have also been several efforts to change the distribution system to reduce geographic disparities. Two of these efforts, Share 15 National and Share 35 Regional were implemented in June 2013. In Share 15 National, adult deceased donor livers are offered nationally to status 1 patients and patients with MELD 15 or higher before local/regional/national patients with MELD scores less than 15 (Table 1). In Share 35 Regional, regional patients with MELD scores above 35 receive offers before local patients below a MELD score of 35. At each MELD score of 35 to 40, local candidates retain priority over regional patients. The threshold of a MELD score of 35 was chosen because of modeling studies suggesting equivalent wait list outcomes of status 1 patients and patients with a MELD score above 35.18

Table 1. United States Adult Deceased Donor Liver Distribution Policy

Share 15	Share 15 National	Share 15 National with Share 35 Regional
Offers for livers are prioritized from top to bottom and are only offered to a lower priority candidate if there are no accepting candidates in previous rows. Share 15 was the distribution strategy until recently. Share 15 National and Share 35 Regional were implemented in Spring 2013.
Local status 1A	Local status 1A	Local status 1A
Regional status 1A	Regional status 1A	Regional status 1A
Regional status 1B	Regional status 1B	Regional status 1B
Local MELD score ≥15	Local MELD score ≥15	Candidates with MELD/PELD scores ≥35 in descending order of MELD score, with local candidates ranked above regional candidates at each level of MELD score
Regional MELD score ≥15	Regional MELD score ≥15	Local MELD score ≥15
Local MELD score <15	National status 1A	Regional MELD score ≥15
Regional MELD score <15	National status 1B	National status 1A
National status 1A	National MELD score ≥15	National status 1B
National status 1B	Local MELD score <15	National MELD score ≥15
National MELD	Regional MELD score <15	Local MELD score <15
	National MELD score <15	Regional MELD score <15
		National MELD score <15

Conclusion

The MELD score drastically changed the liver transplant allocation system in the United States. It was a positive adjustment in the history of liver transplantation, though the system still has significant shortcomings in interregional equitability. Research and debate is ongoing in the liver transplant community regarding what changes to make in the future to improve equitable use of this scarce resource.

References

Source

Study reveals much-needed strategy to protect against deadly liver fibrosis

Public release date: 15-Aug-2013
Contact: Mary Beth O'Leary
moleary@cell.com
617-397-2802
Cell Press

This image demonstrates that the factor IL-33 (brown cells) is present in livers after chronic damage. Credit: Immunity, Mchedlidze et al.

Chronic liver disease is a leading cause of death in the United States, in part because it often causes the formation of harmful scar tissue -- a process known as fibrosis. A study published by Cell Press August 15 in the journal Immunity reveals the central role the immune molecule interleukin 33 (IL-33) plays in the formation of liver fibrosis. The findings suggest that drugs targeting this molecule could serve as a new treatment strategy to protect against liver fibrosis.

"Currently, the therapeutic options for liver fibrosis are limited and not curative," says senior study author Stefan Wirtz of Friedrich-Alexander University Erlangen-Nuremberg. "We identified novel immunological factors that contribute to the development of liver fibrosis, opening up new avenues for the treatment of this serious condition."

Liver fibrosis refers to the accumulation of harmful deposits of extracellular matrix (ECM) proteins, and it can eventually lead to organ failure. Past studies have suggested that this kind of damage is associated with abnormal immune responses in the liver, but very little was known about the molecules and cells that contribute to fibrosis.

In the new study, Wirtz and his team found that the amount of IL-33 in the blood was higher than normal in patients with liver disease. Following up on this observation, they discovered that injection of IL-33 into mice caused ECM proteins to build up in the liver, whereas mice that were genetically modified to lack IL-33 were largely protected from fibrosis. The researchers went on to identify the immune networks underlying IL-33's harmful effects and discovered that this molecule activates immune cells called type 2 innate lymphoid cells (ILC2), which had never before been linked to liver disease.

"Our findings reveal IL-33 as a novel biomarker that could potentially lead to early detection of fibrosis in patients, which may be extremely valuable for preventing further damage to the liver," Wirtz says. "Moreover, the study shows that drugs targeting IL-33 or ILC2 responses could be a promising strategy to protect against fibrosis and chronic liver disease."

####

Immunity, Mchedlidze et al.: "Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis."

Source

Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1-infected patients in Japan: the DRAGON study.

J Gastroenterol. 2013 Sep 5. [Epub ahead of print]

Hayashi N, Seto C, Kato M, Komada Y, Goto S.

Kansai Rosai Hospital, 1-69 Inabasou 3-chome, Amagasaki-shi, Hyogo, Japan, hayashin@kanrou.net

Abstract

BACKGROUND: Efficacy, safety and pharmacokinetics of simeprevir (TMC435), a once-daily, noncovalent, oral hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in combination with peginterferon α-2a/ribavirin (PegIFNα-2a/RBV) for treatment-naïve, HCV genotype 1-infected patients in Japan.

METHODS: In a multicenter, randomized clinical trial in Japan, ninety-two patients received either simeprevir (50 or 100 mg QD) for 12 or 24 weeks with PegIFNα-2a/RBV for 24 or 48 weeks (according to response-guided therapy [RGT] criteria), or PegIFNα-2a/RBV for 48 weeks (PR48 group).

RESULTS: Compared with the PR48 group, plasma HCV RNA reductions in the simeprevir groups were rapid and more substantial (Week 4: -5.2, -5.2 and -2.9 log10IU/mL for simeprevir 50 mg combined, 100 mg combined, and PR48 groups, respectively). High rapid virologic response rates (83, 90, and 8 % for simeprevir 50 mg combined, 100 mg combined, and PR48 groups, respectively) led to high sustained virologic response rates (77-92 %, compared with 46 % for PR48). All but one of the simeprevir-treated patients were eligible to complete treatment after 24 weeks (RGT). Relapse rates in simeprevir-treated patients were low (8-17 %, compared with 36 % for the PR48 group). There were no notable differences in the safety profile between the simeprevir and PR48 groups.

CONCLUSIONS: The addition of simeprevir QD to PegIFNα-2a/RBV, as compared with PegIFNα-2a/RBV alone, demonstrated potent antiviral activity and significantly improved the rates of sustained virologic response, with a shortened 24-week treatment duration, in treatment-naive patients infected with HCV genotype 1 in Japan. Simeprevir was generally safe and well tolerated. (ClinicalTrials.gov number, NCT00996476).

PMID 24005956 [PubMed - as supplied by publisher]

Source

Formal Hepatitis C Education Enhances HCV Care Coordination, Expedites HCV Treatment and Improves Antiviral Response

Liver International

Samali Lubega, Uchenna Agbim, Miranda Surjadi, Megan Mahoney, Mandana Khalili

Liver International. 2013;33(7):999-1007. 

Abstract and Introduction

Abstract

Background & Aims Formal Hepatitis C virus (HCV) education improves HCV knowledge but the impact on treatment uptake and outcome is not well described. We aimed to evaluate the impact of formal HCV patient education on primary provider-specialist HCV comanagement and treatment.

Methods Primary care providers within the San Francisco safety-net health care system were surveyed and the records of HCV-infected patients before and after institution of a formal HCV education class by liver specialty (2006–2011) were reviewed retrospectively.

Results Characteristics of 118 patients who received anti-HCV therapy were: mean age 51, 73% males and ~50% White and uninsured. The time to initiation of HCV treatment was shorter among those who received formal education (median 136 vs 284 days, P < 0.0001). When controlling for age, gender, race and HCV viral load, non-1 genotype (OR 6.17, 95% CI 2.3–12.7, P = 0.0003) and receipt of HCV education (OR 3.0, 95% CI 1.1–7.9, P = 0.03) were associated with sustained virologic treatment response. Among 94 provider respondents (response rate = 38%), mean age was 42, 62% were White, and 63% female. Most providers agreed that the HCV education class increased patients' HCV knowledge (70%), interest in HCV treatment (52%), and provider-patient communication (56%). A positive provider attitude (Coef 1.5, 95% CI 0.1–2.9 percent, P = 0.039) was independently associated with referral rate to education class.

Conclusions Formal HCV education expedites HCV therapy and improves virologic response rates. As primary care provider attitude plays a significant role in referral to HCV education class, improving provider knowledge will likely enhance access to HCV specialty services in the vulnerable population.

Introduction

Hepatitis C virus (HCV) is the most common chronic blood-borne disease and the leading cause of liver transplantation in the US, affecting an estimated 3.2 million Americans.^{[1, 2]} Recent advancement in antiviral treatment options has significantly increased the response rates to anti-HCV therapy even among the difficult to treat populations.^{[3, 4]} Despite this, it is estimated that only 34–48% of chronic carriers are referred for liver specialist assessment,^[5–7] and less than 37% of patients receive treatment for hepatitis C.^[6–8] Therefore, instituting models of care that have the potential to overcome barriers and improve access to care represents a critical goal in addressing the HCV epidemic.^[9] The Institute of Medicine recently released a report identifying 'missed opportunities' in the prevention and control of HCV, and specifically recommended the development, coordination and evaluation of education programs targeting at-risk populations, as well as improved coordination of hepatitis care delivery services in its national strategy to improve hepatitis care services.^[10] In addition, the American Association for the Study of Liver Diseases (AASLD) and Centers for Disease Control and Prevention (CDC) joint conference proceedings on viral hepatitis emphasized the importance of a multidisciplinary approach to HCV care and HCV care coordination, including linkage of infected persons with care and treatment services to improve prevention of viral hepatitis and the effectiveness of treatment.^[8]

Patients within the safety-net healthcare systems that predominantly serve the uninsured and underinsured populations are especially at risk for experiencing health disparities, have limited access to care, and represent a growing vulnerable patient population.^[11] HCV patient education is associated with positive outcomes in various models of HCV care, including increased disease-specific knowledge,^{[12, 13]} interest in treatment,^[14] willingness to accept treatment,^{[5, 15]} and increase liver specialty care clinic attendance.^{[12, 13]} In a prior study within the San Francisco safety-net healthcare system, formal HCV education by liver specialists not only resulted in a significant improvement in HCV knowledge among patients but also appeared to create efficiencies in this healthcare system to allow better access to specialty care for these individuals.^[13] Therefore, this patient-centred approach has the potential to impact HCV management, interest in receipt of HCV treatment and treatment outcome. However, the impact of formal HCV education by specialists on facilitating HCV treatment initiation, adherence to treatment and treatment outcome is not clearly understood. Furthermore, although primary care providers have a pivotal role in identifying patients with HCV, referring patients to specialty consultants for treatment, and collaborating with specialty care providers;^[16] whether formal patient education by a specialist has a positive impact on HCV co-management between primary and specialty care providers has not been previously studied.

Considering the increasing emphasis on systemic improvements to our healthcare delivery system and enhanced coordination of health services, this study was conducted to evaluate the impact of the institution of a mandatory formal HCV education class by liver specialty providers on HCV treatment initiation and outcomes and to evaluate provider attitudes towards the impact of formal patient education on HCV management.

Materials and Methods

This study consists of 1) a retrospective review of electronic medical records of HCV-infected patients before and after the institution of a mandatory HCV education class prior to initiation of treatment, and 2) a cross-sectional survey of primary care providers within the San Francisco safety-net healthcare system. This healthcare system provides services to over 150,000 patients annually including most of the county's uninsured and underinsured population.^[17] This system consists of the San Francisco Community Clinic Consortium, which has ten nonprofit primary care community health centers, and the San Francisco Department of Public Health's Community Health Network, which includes eleven community-based primary care clinics and one acute care hospital with primary care and specialty clinics on-site.^[17] This study was approved by the Committee on Human Research of the University of California San Francisco.

Patient Population

Electronic medical records of HCV-infected viremic patients with elevated HCV viral loads, who underwent pegylated interferon (PEG-IFN) and ribavirin combination antiviral therapy in the liver specialty clinic at San Francisco General Hospital (SFGH) from January 2006 to June 2011 were reviewed. This study period includes the period before and after initiation of a mandatory formal HCV education class (November 2007) by the liver specialty clinic. There were no changes in the liver specialty clinic scheduling procedures or the number of providers within the liver clinics during the entire study period. Data included patient demographics, medical and psychiatric co-morbidities, time to initiation of HCV therapy from first liver specialty clinic visit, adherence to HCV treatment (which included measurement of adherence to clinic visits, medications and recommended laboratory testing and procedures) and viral response to anti-HCV therapy. Adherence to anti-HCV medications was defined as use of ≥80% of pegylated interferon and ≥80% of ribavirin for more than 80% of the expected treatment duration.^[18] Response to anti-HCV therapy was defined as: early virologic response, EVR (>2-log₁₀ decline in HCV RNA viral load by week 12), end of therapy response, ETR (undetectable HCV RNA viral load at end of therapy) and sustained virologic response, SVR (undetectable HCV RNA viral load at 24 weeks following discontinuation of treatment).

Provider Survey Design and Methods

The provider survey instrument was developed by the study investigators with input from hepatologists, survey design experts and previously published surveys. Content domains included provider and practice characteristics, HCV management practices, provider attitudes regarding HCV education, and provider perception of the impact of HCV education on improvement of HCV management, patient-provider communication, patient HCV knowledge, interest in receipt of therapy, patient adherence to HCV management plan, and access to specialty care. The survey was pilot-tested with 20 physicians and revised based on their feedback. The survey was sent to the 248 primary care providers of the San Francisco safety net healthcare system by mail or electronic mail between electronic email between October 15 and December 15, 2011. A second and third mailing to non-respondents was conducted at 4-week intervals.

HCV Education Class

In November 2007, the liver specialty clinic at San Francisco General Hospital instituted a mandatory formal HCV education class accessible to all HCV-infected patients within San Francisco's safety net healthcare system. Providers who wish to refer patients to liver specialty clinic initially schedule patients in the formal HCV education class offered by this specialty service prior to being evaluated in the liver specialty clinic. The patients are directly scheduled for the formal education class by the primary providers (direct access) based on patient's availability and the classes are offered every 2 weeks. The HCV education class consists of a 2-hour standardized in-person PowerPoint presentation delivered by a liver clinic nurse practitioner. Each class has approximately 25–30 participants and is offered in English and any other languages by using certified interpreters as needed. The class provides information on HCV transmission, diagnosis, symptoms, natural history, severity of liver disease, appropriate candidacy for treatment, response rates of antiviral therapy and side effects of treatment.

Statistical Analysis

Patient data analysis. Patient characteristics were summarized using mean ± SD, median (range) and frequencies. To evaluate patient factors associated with the outcomes SVR and time to initiation of HCV therapy, univariate analysis was performed using Chi-square test (Fisher's exact test when appropriate) for categorical variables and Mann-Whitney test for continuous variable. Multivariable regression modelling evaluating factors associated with SVR and time to initiation of therapy included predictors from an a priori compiled list as well as those with a p value <0.05 as determined by the univariate analysis.

Provider survey data definition and analysis. Provider and practice characteristics were summarized using mean ± SD, median (range) and frequencies. The provider attitude score towards impact of formal HCV education class on HCV management was determined by summing the numerical codes assigned to responses to eleven questions assessing provider attitudes as follows: 4 to an 'strongly agree' response, 3 to an 'agree' response, 2 as 'neither agree or disagree', 1 as 'disagree' and 0 as 'strongly disagree.' Univariate regression analysis was performed to evaluate provider and practice characteristics associated with formal HCV education class. Multivariable regression modelling evaluating factors associated referral to HCV education class included predictors from an a priori compiled list as well as those with a p value <0.05 as determined by the univariate analysis.

For all analysis, statistical significance was assessed at the p-value of <0.05 level (2-sided) in all models. All analysis was performed using SAS version 9.2 (SAS Institute, Inc., 2007, Cary, NC, USA).

Results

Patient Characteristics

During the study period, of the 551 HCV-infected patients who attended the liver specialty clinic, 118 treatment eligible patients underwent antiviral therapy. The overall treatment rates (24% vs 19%, p = 0.1) were similar before and after HCV education class initiation. Patient characteristics of treated and untreated groups were similar with respect to age (50 vs 50, p = 0.43), male gender (62% vs 65%, p = 0.52) and White race (48% vs 39%, p = 0.058). Mode of HCV transmission was predominantly injection drug use in both groups (59% vs 69%, p = 0.25).

Table 1 summarizes the overall patient characteristics of those who underwent antiviral therapy and characteristics by receipt of formal HCV education class. Overall, the majority of patients were middle-aged and approximately half of patients were minorities. Injection drug use (IDU) was the most common HCV risk factor in both groups (59%), and nearly all patients were treatment naïve (94%). Although there was a lower proportion of men among those who received HCV education (50% vs 74%, p = 0.008), other patient and viral characteristics were similar amongst those who did and did not receive formal HCV education.

Table 1.  Characteristics of patients who did or did not undergo formal hepatitis C virus (HCV) education

Patient characteristic	Overall (N = 118)	Patients who did not receive HCV education (n = 58)	Patients who received HCV education (n = 60)	P- value*
Age (years), median (quartiles)	51 (42–58)	50 (41–57)	51 (44–58)	0.69
Males (%)	73 (62)	43 (74)	30 (50)	0.008
Race/ethnicity (%)
White	57 (48)	26 (45)	31 (52)	0.90
African American	11 (9)	6 (10)	5 (8)
Latino	22 (19)	11 (19)	11 (18)
Asian/Pacific Islander	28 (24)	15 (26)	13 (22)
English as primary language (%)	84 (71)	39 (67)	45 (75)	0.42
Uninsured (%)	57 (48)	25 (43)	32 (53)	0.28
Income < $15 000 per year (%)	83 (75)	38 (68)	45 (82)	0.13
Concurrent substance abuse treatment (methadone, buprenorphine) (%)	8 (7)	5 (9)	3 (5)	0.49
Duration of HCV infection (years), median (range)	20 (2–52)	21 (2–47)	19 (2–52)	0.75
Prior history of IDU (%)	56 (59)	27 (54)	29 (64)	0.40
HIV coinfection (%)	15 (13)	10 (17)	5 (8)	0.17
HBV coinfection (%)	5 (4)	4 (7)	1 (2)	0.20
Psychiatric comorbidities	47 (40)	24 (41)	23 (38)	0.85
Serum ALT (Units/mL), median (range)	68 (18–586)	72.5 (18–257)	63.5 (18–586)	0.34
Log10 HCV viral load (IU/mL), median (range)	5.9 (3.9–7.1)	5.9 (3.9–6.7)	6.0 (4.3–7.1)	0.43
HCV genotype (%)
1	66 (56)	34 (59)	32 (53)	0.51
2	22 (19)	12 (21)	10 (17)
3	25 (21)	9 (16)	16 (27)
Other	5 (4)	3 (5)	2 (3)
Inflammation grade on histology**(%)
<2	15 (19)	8 (17)	7 (22)	0.77
≥2	63 (81)	38 (83)	25 (78)
Fibrosis stage on histology**(%)
<2	21 (27)	14 (30)	7 (22)	0.45
≥2	57 (73)	32 (70)	25 (78)
Steatosis on histology**(%)	32 (41)	17 (37)	15 (47)	0.48
Treatment naïve (%)	111 (94)	53 (91)	58 (97)	0.27
Early virologic response (%)	93 (88)	42 (82)	51 (93)	0.14
End of treatment response (%)	90 (83)	43 (80)	47 (87)	0.44
Sustained virologic response (%)	61 (59)	27 (50)	34 (68)	0.07
Early discontinuation of therapy because of side effects† (%)	9 (8)	7 (12)	2 (3)	0.09
Adherence to clinic visit (%)	100 (87)	51 (88)	49 (86)	0.79
Adherence to medications (%)	102 (88)	51 (88)	51 (86)	1.0
Adherence to procedures (%)	103 (90)	52 (90)	51 (90)	1.0
Time to initiation of therapy (days), median (quartiles)	184 (102–316)	284 (147–431)	136 (88–212)	<0.0001

*P-value refers to the comparison of patients who did and did not receive formal HCV education; statistical significant was designated at P < 0.05 (2-sided).

**Liver biopsy was performed in 78 patients.

†A total of 30 patients discontinued therapy early.

IDU, Injection drug use; HIV, Human Immunodeficiency Virus; HBV, Hepatitis B Virus; ALT, alanine aminotransferase.

With respect to HCV antiviral therapy, although overall adherence to HCV therapy and clinic visits was high (>85%) in those who underwent therapy, there were higher rates of SVR among those who received formal HCV education (68% vs 50%), lower rates of discontinuation of HCV antiviral therapy because of side effects (3% vs 12%), and lower virologic relapse rates following discontinuation of therapy (16% vs 28%), but these did not reach statistical significance. The overall higher rates of SVR observed in this safetynet system is related to the lower proportion of genotype 1 patients (56%) than that reported for the general US population.

Host and Viral Factors Associated With Treatment Initiation and Treatment Outcomes

On univariable analysis, the time to initiation of HCV treatment from initial liver clinic visit date was significantly shorter among those who received formal HCV education compared to those who did not (median 136 vs 284 days, p < 0.0001) (Table 1). On multivariable analysis time to initiation of therapy was negatively associated with receipt of formal HCV education, when controlling for patient age, gender, race and HCV genotype (coef -182, 95%CI -272 to -92 days, p < 0.0001), and also when accounting for severity of liver disease (fibrosis stage >2) on liver biopsy (coef -123, 95%CI -233 to -14 days, p = 0.028).

With respect to treatment outcome, factors associated with achieving SVR on univariate analysis included non-1 genotype HCV (OR 5.4, 95%CI 2.1–15.0 p = 0.0002) and higher grades of inflammation on histology among patients who had a liver biopsy (OR 4.5, 95%CI, 1.3–16.2, p = 0.022). On multivariable analysis (Table 2), when controlling for age, gender, race and baseline HCV viral load, non-1 genotype HCV and receipt of formal HCV education were independently associated with SVR. In addition, accounting for adherence to antiviral therapy did not significantly alter these odds ratios. In the subset of patients who had undergone a liver biopsy prior to HCV therapy, higher grade of liver inflammation (OR 5.9 95%CI 1.3–26.6 p = 0.02) and lower stage of fibrosis (OR 0.23, 95%CI 0.05–0.95, p = 0.043) in addition to non-1 HCV genotype (OR 6.0, 95%CI, 1.6–22.6 p = 0.008) were significantly associated with achieving SVR when controlling for age, gender, race and baseline HCV viral load. Once again, adherence to antiviral therapy did not significantly alter these odds ratios.

Table 2.  Multivariate analysis of factors associated with sustained virologic response to hepatitis C virus (HCV) antiviral therapy

Variables	Odds Ratio	95% CI*	P value**
Age per decade	0.7	0.4–1.1	0.12
Female gender	0.6	0.2–1.8	0.36
Race (vs White)
African-American	0.8	0.2–4.2	0.80
Latino	0.4	0.1–1.4	0.14
Asian/Pacific Islander	1.5	0.5–4.7	0.51
HCV non-1 genotype (vs genotype 1)	6.2	2.3–16.7	0.0003
Log10 HCV viral load (IU/mL)	0.8	0.3–2.1	0.72
Receipt of formal HCV education	3.0	1.1–7.9	0.031

*95% confidence interval.

**Statistical significance was designated at P < 0.05.

Provider and Practice Characteristics

Out of 248 providers, 94 (38%) responded to the survey. Provider characteristics are summarized in Table 3. The mean age of providers was 42, and the majority was White and female. Most providers held an MD degree and ~40% were in practice for more than 10 years. The median proportion of White patients in practices was 25%, the median proportion of patients with limited English proficiency was 50%, and the median proportion of uninsured patients in practices was reported at 50%.

Table 3.  Provider and practice characteristics in the San Francisco safety net healthcare system (n = 94)

Provider and practice characteristic
Age (mean ± SD) (years)	42 ± 11
Male (%)	25 (27)
Race/ethnicity (%)
White	58 (62)
African American	3 (3)
Latino	5 (5)
Asian American/Pacific Islander	24 (26)
Other	3 (3)
Post-graduate degree (%)
MD	68 (72)
Nurse practitioner	24 (26)
Physician's assistant	2 (2)
Specialty (%)
Internal medicine	48 (51)
Family practice	31 (33)
Infectious disease	1 (1)
HIV	8 (9)
Other	6 (6)
Years in practice
0–10	55 (58.5)
11–20	24 (25.5)
>20	15 (16)
Number of patients seen per week (%)
0–20	35 (37)
21–40	28 (30)
>40	31 (33)
Median proportion of patients by race
White	25
African-American	20
Latino	25
Asian/Pacific Islander	20
Other	2
Median proportion of patients with limited English proficiency	50
Median proportion of patients in practice with
Private or public insurance	50
Uninsured	50

HCV HCV Management Practices

Provider HCV management practices are summarized in . Nearly one quarter of providers reported that HCV patients comprised more than 25% of their practice population. Among HCV patients, the reported mode of transmission for HCV was IDU in more than 80% of patients and ~20% of providers reported current alcohol or illicit drug abuse in over half of their HCV patients. A rate of greater than 10% co-infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) among HCV patients was reported by 30% and 17% of providers respectively. Over 75% of providers reported that at least half of their HCV patients have been vaccinated against hepatitis A and hepatitis B, and only 17% reported that more than 25% of the HCV patients had received HCV antiviral therapy.

Table 4.  Hepatitis C virus (HCV) management practices among the San Francisco safety net providers

IDU, Injection drug use; HAV, Hepatitis A Virus; HBV, Hepatitis B Virus; HIV, Human Immunodeficiency Virus.
Practice with more than 25% HCV patients	24
Proportion of HCV patients with history of IDU in practice	85
Proportion of HCV patients in practice who have been vaccinated against HAV
≤25%	13
26–50%	12
51–74%	10
≥75%	65
Proportion of HCV patients in practice who have been vaccinated against HBV
≤25%	9
26–50%	10
51–74%	13
≥75%	68
Proportion of HCV patients in practice who are coinfected with HIV
≤25%	79
26–50%	7
51–74%	1
≥75%	13
Proportion of HCV patients in practice coinfected with HBV
≤25%	98
>25%	2
Proportion of HCV patients in practice currently abusing alcohol or illicit drugs
≤25%	45
26–50%	32
51–74%	9
≥75%	14
Proportion of HCV patients in practice currently undergoing outpatient substance abuse therapy
≤25%	80
26–50%	15
51–74%	0
≥75%	5
Proportion of HCV patients in practice who have received HCV antiviral therapy
≤25%	83
26–50%	9
51–74%	1
≥75%	7

Provider Attitudes Towards Formal HCV Education Class

Nearly all providers (90%) reported being aware of the presence of a formal HCV education class by the liver specialty clinic, and 40% of providers had referred at least half of their HCV patients to the HCV education class. The most common reasons for patient referral to class were to receive general education about HCV disease (62%) and to receive HCV therapy (57%). The most common reasons for not referring patients to the education class were patients' lack of interest in HCV therapy (54%), followed by coexisting psychiatric contraindication to HCV therapy (47%), and ongoing alcohol and/or drug abuse (46%).

Provider attitudes towards the impact of the formal HCV education class on HCV management within their practices are summarized in . On average, a majority of primary care providers agreed that the formal HCV education class increased their patients' HCV knowledge and interest in receipt of HCV treatment. Over half of providers also agreed that the class improved patient communication regarding HCV disease and patient understanding of HCV-related resources. In addition, over half of providers reported that formal HCV education resulted in overall improved management of HCV patients and has helped them address patient concerns about their disease. Moreover, more than 40% of providers agreed that formal HCV education has improved primary care-specialist HCV co-management and increased access to liver specialty care.

Table 5.  Impact of formal hepatitis C virus (HCV) education class on provider practices

Impact of education class	Agree (%)	Neutral (%)	Disagree (%)
Improved my patients' knowledge of HCV disease	70	26	4
Increased patients' interest in being treated for HCV	52	39	9
Increased adherence to HCV-related medical testing such as blood tests, imaging, liver biopsy, clinic visits	30	64	6
Improved patients' understanding of available resources for HCV care within the San Francisco safety net system	55	35	10
Increased my patients' level of interest in substance abuse (illicit drugs, alcohol) therapy	21	65	14
Improved my patient's adherence to my management plan recommendations for other medical conditions (such as hypertension, diabetes, etc.)	23	62	15
Resulted in improved patient communication with me regarding HCV	56	35	8
Helped me better address patient's concerns regarding HCV disease and its management	53	41	6
Overall improved the management of my patients with HCV in my practice	54	39	7
Made it easier for me to co-manage my patients with liver specialty care providers	44	45	11
Increased the access to liver specialty care in our safety net system	41	46	13

Provider and Practice Factors Associated With Referral Rates to Formal HCV Education Class

On univariable analysis, the proportion of patients with HCV in practice (coef -21.2, 95%CI -37.5 to -4.9 percent, p = 0.012), the proportion of uninsured patients in practice (coef 0.65, 95%CI 0.15–1.2 percent, p = 0.012), a positive provider attitude towards the impact of HCV class in practice (coef 1.2, 95%CI -0.13 to 2.6 percent, p = 0.075), and not possessing an MD degree (coef -6.2, 95%CI -12.3 to -0.19 percent, p = 0.044), were associated with referral of patients to the formal HCV education class. On multivariable analysis (), when controlling for provider age, gender and degree, only a positive provider attitude towards the impact of the HCV class was independently associated with higher rates of referral to formal HCV education class.

Table 6.  Multivariate analysis of provider and practice factors associated with referral to formal hepatitis C virus (HCV) education class

Variables	Coefficient	95% CI	P value
Provider age	0.5	−0.4–1.3	0.29
Provider female gender	11.9	−9.0–32.8	0.26
Provider degree
Non-MD (vs MD)	4.3	−3.4–12.0	0.27
Proportion of HCV patients in practice	−15.9	−36.1–4.2	0.12
Proportion of uninsured patients in practice	0.6	−0.1–1.3	0.071
Provider attitude towards impact of formal HCV education class	1.5	0.1–2.9	0.039

Discussion

This is the first study to evaluate the impact of formal HCV patient education on receipt of HCV therapy, treatment outcomes and primary provider HCV management practices in a safety-net healthcare system. We have shown that formal HCV education expedites receipt of HCV antiviral therapy and is associated with higher rates of virologic response to HCV treatment. In addition, a majority of providers reported that the formal HCV education class improved their patient's knowledge, communication, interest in therapy, understanding of resources for HCV management and improved the overall management of the HCV-infected patients in their practice. Furthermore, a positive provider attitude towards the impact of formal HCV education was associated with higher rates of patient referral to the HCV education class.

The vulnerable patient population within the safety-net healthcare system is disproportionally affected by HCV and adverse disease outcomes[11]. A prior study in this healthcare setting has shown that formal HCV education class results in improvement of patient's HCV knowledge across all ages, racial groups, education backgrounds and socioeconomic status.^[13] Prior studies have also shown that HCV patients consider HCV education an important healthcare need that results in a marked increase in willingness to accept treatment.^{[15, 19]} In this study, the majority of primary providers also perceived that their patients' HCV knowledge had increased as a result of participation in the class. In addition, over half of providers reported that HCV education class increased their patient's interest in HCV treatment. Moreover, the HCV class appeared to improve patient's understanding of available resources for HCV care within the healthcare system, improved patient-provider communication, assisted providers in addressing patients' concerns regarding HCV disease, and improved overall HCV management within the primary care practice by provider report. These findings are important in that while primary care providers often feel confident in their ability to screen for HCV and provide initial HCV disease evaluation, and believe they should be involved in HCV co-management with specialists, they feel less confident about HCV monitoring and treatment [20–22]. Therefore, in addition to their patient's direct benefit in receipt of education, they too may benefit from additional resources and support in these areas.^{[20, 21]} Indeed, approximately 40% of providers also reported that HCV education class facilitated HCV co-management within their practices and increased access to liver specialty care services.

Interestingly, in this study primary providers did not report a significant increase in patient adherence to HCV management plans or interest in substance abuse therapy within their practices. In the practices surveyed in this study approximately 25% of providers indicated that over 25% of patients within their practice were infected with HCV. In contrast, in a national survey of primary providers, 73% of respondents had reported caring for 5 or less HCV-infected patient within the past year.^[23] Given the high prevalence of HCV infection within practices in the San Francisco safety-net healthcare setting, it is possible that our providers had previously implemented their own mechanisms within practices to effectively address substance abuse therapy and adherence to HCV monitoring.

Whether the observed improvement in patient's knowledge and the positive impact on provider practices following formal HCV education actually influences HCV treatment initiation and treatment outcomes has not been previously studied. We have found that the time to initiation of HCV therapy was reduced by half in those patients who underwent formal HCV education compared to those who did not receive disease-specific education. This patient-centred approach to HCV education may have resulted in faster uptake of treatment by helping motivated patients to self-identify, more actively participate in their medical decision-making,^{[24, 25]} and overcome treatment-related fears that impede or delay antiviral therapy.^[26] This also suggests that the education class has resulted in efficiencies within this resource-limited healthcare system that allow better utilization of specialty care services in this population.

HCV education appears to improve adherence to HCV therapy.^{[27, 28]} However, there are only limited studies evaluating the role of patient education on HCV treatment outcome. In a study by Cacoub et al., there was a 7% increase in the rate of SVR and 6% decrease in rates of virologic relapse among those received support documents and educational material during individual sessions compared to those who did not receive disease specific education, but these findings did not reach statistical significance.^[27] Larrey et al. assessed the impact of ongoing patient education during HCV therapy. In that study, the odds of achieving SVR were 2.5 times higher among patients who received systematic consultation by a nurse regarding patient adherence and the efficacy of therapy compared to those who did not receive the education.^[29] Similarly, we have shown that a formal HCV education class prior to HCV treatment resulted in an 18% increase in rates of SVR, and patients who received education were three times more likely to achieve SVR, independent of medication adherence and patient or viral factors. It is known that adherence to anti-HCV medications impacts rates of response to therapy. We did not observe a significant difference in patient adherence to medications in those who did and did not receive patient education. The overall rates of adherence to medication by self-report was high at 88% in this study, similar to that reported in other HCV populations ranging from 76–89%.^[30] However, our study did show that patients who attended formal HCV education were less likely to discontinue treatment because of side effects (3% vs 12%), one of the most common reasons for early discontinuation of treatment in several prior studies [9, 31, 32]. Higher rates of early discontinuation of therapy and delay in initiation of treatment in those who did not undergo HCV education, can potentially contribute to lower rates of SVR observed in this population.

The recent single topic conference cosponsored by the AASLD and CDC has emphasized the value of 'systemic changes in our healthcare delivery system and enhanced coordination of prevention and care services through education of the public and healthcare providers, and linkage of infected persons with care and treatment services to successfully prevent viral hepatitis and increase treatment efficacy'[8]. Primary care providers play a significant role in linkage of HCV-infected persons to available HCV care and treatment services. Limited data, predominantly in the HIV-HCV co-infection setting, suggest that provider attitudes affect rates of both provider HCV treatment recommendation and patient uptake of HCV treatment.^{[33, 34]} A national survey of family physicians has also shown that having a positive attitude regarding HCV care in the primary care setting was associated with more provision of HCV care services.^[21] Moreover, patients interpret a lack of referral to HCV specialty care or discussion of treatment by primary care providers as an indicator that pursuit of HCV treatment should not be considered a priority.^[35] We have shown that a positive provider attitude towards the impact of HCV education is independently associated with higher rates of referral to formal HCV education class. Therefore, increasing provider understanding of the impact of patient education on HCV care and treatment outcomes will be essential to improving patient access to HCV care services and success of antiviral therapy.

The main limitation of this study is the retrospective patient data collection, while the primary strengths include long-term patient follow-up and prospective assessment of provider attitudes and practices. Because the formal HCV education class was instituted as a mandatory component of referral of HCV patients to the liver specialty clinic, the study was limited by a lack of randomization of patients to education vs no education class when evaluating treatment outcomes. However, we were able to utilize a historical control of HCV patients prior to the initiation of education class to compare HCV treatment outcomes. Both the formal HCV education patient cohort and the historical controls likely represent individuals who are motivated to receive HCV therapy and management. Therefore, selection bias is unlikely to play a role in our finding that HCV education significantly impacts time to initiation of HCV therapy and HCV antiviral response. In addition, as the anti-viral therapy regimen (pegylated interferon in combination with ribavirin), the treating providers, and the liver specialty clinic scheduling procedures did not change before and after institution of formal HCV education, it is unlikely that differences in antiviral therapy management practices or scheduling practices overtime would impact the findings. Generalization to other non-safety-net practice settings may also be limited; nevertheless, our results present a potentially effective intervention to improve linkages to HCV specialty care, HCV treatment uptake and treatment outcome.

In summary, formal HCV education by liver specialists creates efficiencies in resource-limited healthcare systems, which not only allows better access to specialty care and treatment services but also improves HCV antiviral effectiveness. Provider attitudes towards the impact of HCV patient education play a significant role in referral to these services. Along with improvements in the healthcare delivery system, interventions directed at increasing provider knowledge of HCV disease and the important role of patient education in improving HCV management will likely enhance HCV care coordination and ultimately amplify the success of antiviral therapy, particularly in vulnerable populations.

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