a b s t r a c t

Background: FIB-4, a non-invasive serum fibrosis index (which includes age, ALT, AST, and platelet count), is fre- quently available during ED visits. Our objective was to define 1-year HCV-related care outcomes of ED patients with known HCV, for the overall group, and both those with and without advanced fibrosis.

Methods: As part of an ongoing HCV linkage-to-care (LTC) program, HCV-infected ED patients were identified ret- rospectively via medical record review. Components of FIB-4 were abstracted, and patients with an FIB-4 N 3.25 were classified with advanced fibrosis and characterized with regards to downstream HCV care continuum out- comes at one-year after enrollment.

Results: Of the 113 patients with known HCV, 38 (33.6%) had advanced fibrosis. One-year outcomes along the HCV care continuum after ED encounter for ‘all’ 113, 75 ‘without advanced fibrosis’, and 38 ‘advanced fibrosis’ patients, respectively, were as follows: agreeing to be linked to care [106 (93.8%), 72 (96.0%), 34 (89.5%)]; LTC

[38 (33.6%), 21 (28.0%), 17 (44.7%)]; treatment initiation among those linked [16 (42.1%), 9 (42.9%), 7

(41.2%)]; sustained virologic response 4 weeks post-treatment among those treated [15 (93.8%), 9 (100.0%), 6 (85.7%)]; documented all-cause mortality [10 (8.8%), 3 (4.0%), 7 (18.4%)]. Notably, 70% of those who died had ad- vanced fibrosis. For those with advanced liver fibrosis, all-cause mortality was significantly higher, than those without (18.4% versus 4.0%, p = 0.030).

Conclusions: Over one-third of HCV-infected ED patients have advanced liver fibrosis, incomplete LTC, and higher mortality, suggesting this readily-available FIB-4 might be used to prioritize LTC services for those with advanced fibrosis.

(C) 2018

1. Background

The Centers for Disease Control and Prevention (CDC) estimates that

2.3-3.7 million Americans are living with chronic Hepatitis C virus (HCV) [1]. Among individuals chronically infected with HCV, without effective treatment, up to 7% will die from liver cirrhosis or hepatocellu- lar carcinoma, typically occurring after 20 to 30 years of progressive liver fibrosis [2]. Furthermore, in recent years, HCV-related mortality has surpassed the total number of deaths from 59 other nationally noti- fiable Infectious conditions combined which includes human immuno- deficiency virus (HIV) [3].

The burden of HCV infection in emergency department (ED) patients is significant because EDs serve as a medical safety net for many Americans, who are also at high risk for HCV. Several seroprevalence

* Corresponding author at: Johns Hopkins University Department of Emergency Medicine, 5801 Smith Avenue, Suite 3220 Davis Building, Baltimore, MD 21209, United States.

E-mail address: [email protected] (Y.-H. Hsieh).

studies conducted in urban EDs have reported extremely high preva- lence of HCV antibodies, ranging from 13 to 18% [4-7]; many of these pa- tients remain unaware of their HCV serostatus, and/or their virologic status. Additional data highlighting the burden of HCV among ED pa- tients comes from a 10-year healthcare utilization survey (2001

-2010) which estimated approximately three-quarter million HCV- related ED visits [8]. The Disease burden and clinical challenge associ- ated with delivering testing and linkage-to-care (LTC) services in the episodic care environment of the ED is significant. Numerous experts have reported that the limitED capacity of specialty care services to take new patients across the nation, represents a major public health challenge [7,9,10]. For individual patients, the impact is manifested by long back logs of wait times for in-take appointments (N6 months), and frequent failures to LTC after the ED encounter [11]. Ultimately, these lead to suboptimal outcomes along the HCV care continuum for the ED HCV-infected population, which have particularly important ad- verse implications for those with advanced stage liver disease [12].

Up until now, the EDs role in addressing the clinical and public health challenges of untreated HCV has focused exclusively on

https://doi.org/10.1016/j.ajem.2018.08.067

0735-6757/(C) 2018

identifying those who are infected, and offering referral for LTC. Consid- ering the fact that limited resources exist for LTC services for ED patients who have chronic HCV, a new paradigm is required, which prioritizes LTC and treatment services for those in greatest need of prompt HCV care; such an approach could represent a significant improvement over the existing standard of care (non-prioritized LTC services rou- tinely offered out of EDs currently across the US). The simple non- invasive liver fibrosis serum index, FIB-4 [13], which combines age with commonly-available laboratory values [(platelets, alanine amino- transferase (ALT), aspartate aminotransferase )], has been vali- dated for estimating liver fibrosis stage and could provide a simple pragmatic risk stratification tool to help prioritize HCV LTC processes.

Our primary aim was to determine the outcomes of the downstream HCV care continuum among ED patients with known chronic HCV infec- tion, one year after standard of care (i.e. non-prioritized) HCV LTC ser- vices were provided. Our secondary aim was to determine if those with advanced liver fibrosis (retrospectively estimated using the non- invasive FIB-4 index) was associated with inadequate downstream care continuum outcomes.

1. Methods

The study site is the urban adult XXX Hospital ED (XXXED) with ap- proximately 70,000 annual visits. The ED serves a predominantly socio- economically disadvantaged population with high risk for HCV infection. A seroprevalence study estimated approximately 8% of pa- tients in this ED had chronic HCV infection [7]. This study was con- ducted as a quality improvement evaluation of an ED-based HCV LTC program with approval from The XXX University School of Medicine In- stitutional Review Board.

From March 10, 2015 to November 17, 2015, a pilot HCV LTC pro- gram was initiated. Potentially eligible participants for the program were ED patients with chronic HCV infection, defined as having a posi- tive HCV RNA in the electronic medical record (EMR). Dedicated paid staff who were trained as patient care navigators by RER (Emergency Medicine) and RI (Infectious Diseases), approached those patients de- termined to have chronic HCV, and offered them expedited LTC ap- pointments at The XXX viral hepatitis Clinic (XXVHC). If the patient was interested in being linked, the ED patient navigators contacted case managers from the XXVHC who either came directly down to the ED to meet the patient (if the patient was in the ED during XXVHC op-

The equivalent of transient elastography to advanced fibrosis (F3-F4) is a value greater than or equal to 9.5 kPa [20]. Mortality documented on EMR was further categorized, as likely liver-related or not based on the final diagnosis and the physician notes of the evaluating Infectious diseases specialist, who is also the medical director of the JHVHC (co-au- thor MSS).

Chi-squared tests or Fisher exact tests for categorical data and t-test for continuous data were performed to determine differences in preva- lence of advanced liver fibrosis by socio-demographic status using SAS

9.4 (SAS Institute Inc., Cary, North Carolina). All-cause mortality in 1000 person-years among patients with known chronic HCV infection one year after enrollment were calculated and compared to a group of randomly selected, 1:1 ratio, age-, sex-, race-matched ED patients. The dataset used for the comparison group was, for feasibility and conve- nience purposes, was taken from an identity-unlinked blood-borne pathogen seroprevalence study carried out around the same time as this study between December 2015 and January 2016. The identity- unlinked seroprevalence study was approved by The XXX University School of Medicine Institutional Review Board.

1. Results

During the 8-month study period, a total of 114 ED patients with anti- HCV antibodies and HCV RNA (or documented clinical viral hepatitis C di- agnosis) were approached by patient care navigators. The majority of pa- tients were male (62.3%), African American (79.0%), and aged 50 years and older (71.9%). Twenty-six (22.8%) patients were co-infected with HIV. Among 114 patients identified as being HCV RNA positive, 113 (99.1%) had sufficient data collected as part of routine medical care prac- tice to allow calculation of an FIB-4 score and were included for further analysis (Table 1). Median and mean FIB-4 scores were 2.26 (IQR: 1.41 to 4.68) and 4.62 (SD: 12.27). There were 38 (33.6%) patients with FIB-4 score N 3.25 (i.e. advanced fibrosis). Comparing those with FIB-4 N 3.25 and <= 3.25, there were no differences with regard to sex, race, or HIV sta- tus. However, as expected, those with FIB-4 N 3.25 were significantly older than those with lower scores (FIB-4 N 3.25: 57.2 +- 7.5 years, FIB-4 <= 3.25: 52.6 +- 10.0 years, p = 0.013).

Table 1

Characteristics of 113 patients with chronic hepatitis C viral infection by FIB-4 index in an urban emergency department

eration hours) or contacted the patient by phone the next business day (if the patient was in the ED during non-business hours) to arrange an expedited LTC appointment. Patient demographics and blood labora- tory test values within 6 months of the encounter date, including ALT, AST, and platelet count, were obtained from the EMR from the ED visit. FIB-4 scores were calculated using the following formula:

Characteristics Total

population

n (%)

FIB-4 <=

3.25

n (%)

FIB-4 N

3.25

n (%)

Age (years) x AST (U/L)

Total number Age (years)?	113	75	38
18-44	15 (8.8)	12 (16.0)	3 (7.9)
45-54	44 (38.9)	34 (45.3)	10 (26.3)
55-64	41 (36.3)	21 (28.0)	20 (52.6)
>=65	13 (11.5)	8 (10.7)	5 (13.2)
Gender Male	70 (61.9)	45 (60.0)	25 (65.8)
Female	43 (38.1)	30 (40.0)	13 (34.2)
Race Black	89 (78.8)	61 (81.3)	28 (73.7)

FIB-4 = Platelet count 10⁹ L ALT U L

1/2

/ x [ ( / )]

FIB-4 scores were calculated and then mapped to a F0-F4 equivalent

scale [14]. In using FIB-4, a score of N3.25 is characterized as F3-F4, or ad-	White	20 (17.7)	12 (16.0)	8 (21.0)
vanced liver fibrosis. One year after each patient’s original encounter	Declined	4 (3.5)	2 (2.7)	2 (5.3)

date, a retrospective chart review was carried out to determine HCV- related clinical information, including LTC status, liver Fibrosis staging by ultrasound-based transient elastography (FibroScan) [15], fibrosis

HIV Status HIV +	25 (22.1)	14 (18.7)	11 (28.9)
HIV - linkage to care	88 (77.9)	61 (81.3)	27 (71.1)

staging biomarker test (FibroSure) [16], or other modalities, initiation	Agreed to linkage	106 (93.8)	72 (96.0)	34 (89.5)
of HCV antiviral treatment, sustained viral response 4 weeks post-	Attended 1st appointment	38 (33.6)	21 (28.0)	17 (44.7)

treatment (SVR4), as well as reported mortality. SVR4 was used to serve as an initial measure of treatment success instead of SVR12, a def- inite measure for virologic cure at 12 weeks post-treatment [17-19], given the anticipated challenges with follow-up from this urban ED pop- ulation, and the pilot nature of this study. SVR4 is considered an accept- able initial measure of treatment success in HCV clinical trials [17-19].

Treatment initiated 16 (14.2) 9 (12.0) 7 (18.4)

Sustained viral suppression 15 (13.3) 9 (12.0) 6 (15.8)

Deceased within 1 year after the initial encounter⁺

Yes 10 (8.8) 3 (4.0) 7 (18.4)

* p = 0.047.

⁺ p = 0.030 (Fisher’s exact test).

We examined varied steps along the HCV care continuum as follows: “Agree to Linkage”, “Linked to Care”, “Liver Fibrosis Staging”, “Treatment - Initiated”, and “Sustained Virologic Response, SVR4”. Outcomes of the care continuum were evaluated for the overall group of patients (n = 113), as well as for those with advanced liver disease (n = 38) catego- rized by FIB-4, and those without advanced liver disease (n = 75). For the overall group of patients (see Fig. 1), 106 (93.8%) patients agreed to be linked to HCV care in the ED; 38 (33.6%) made their first scheduled ap- pointment at the JHVHC; 36 (31.9%) had liver fibrosis staging; 16 (14.2%) initiated HCV antiviral treatment within 1 year; 15 (13.3%), including 3 patients who did not complete treatment course, had a non-detectable viral load after the treatment and had sustained virologic response at least four weeks (SVR4) after the completion of treatment course. For the group of 38 patients with advanced liver fibrosis (see Fig. 1), 34 (89.5%) patients agreed to be linked to HCV care in the ED; 17 (44.7%) made their first scheduled appointment at the JHVHC; 8 (21.1%) had tran- sient elastography for liver fibrosis staging; 7 (18.4%) initiated HCV anti- viral treatment within 1 year; 6 (15.8%) completed an antiviral Treatment regimen; 6 (15.8%) had a non-detectable viral load after the treatment and had sustained virologic response at least four weeks (SVR4) after the completion of treatment course. For the group of 75 pa- tients without advanced liver fibrosis (see Fig. 1), 72 (96.0%) patients agreed to be linked to HCV care in the ED; 21 (28.0%) made their first scheduled appointment at the JHVHC; 19 (25.3%) had transient elastography for liver fibrosis staging; 9 (12.0%) initiated HCV antiviral treatment within 1 year; 6 (8.0%) completed an antiviral treatment regi- men; 9 (12.0%), including 3 patients who did not complete treatment course, had a non-detectable viral load after the treatment and had sustained virologic response at least four weeks (SVR4) after the comple- tion of treatment course.

Among the 22 patients who were linked to care but did not receive HCV treatment within one year of ED encounter [which included 10 (45.5%) with advanced fibrosis], six were lost follow-up [1 advanced fi- brosis], six had HCV antiviral treatment deferred due to severe comor- bid diseases [all advanced fibrosis; three deceased; two within one year of ED encounter; 1 due to liver disease], four were denied HCV an- tiviral treatment by insurers due to absent or mild fibrosis (F0 or F1) [0 advanced fibrosis], four received antiviral treatment one year after the ED encounter [2 advanced fibrosis; including one who did not fill the antiviral prescription and was lost follow-up], one moved to another state [1 advanced fibrosis], and one was observed to have self-cleared (i.e. undetectable viral load without treatment) [0 advanced fibrosis].

At one year post-enrollment date, at least 10/113 (8.8%) patients

were deceased [[i.e. mortality: 88.5 per 1000 person years (PYs)] iden- tified from the medical chart]. 67 patients were confirmed still alive

by chart review, and the remaining 36 had no data in the medical chart available to ascertain whether they were alive or deceased. Of those who died, four (40%) were likely due to liver-related complica- tions of which all had advanced liver fibrosis and three were not treated. Advanced liver fibrosis defined by FIB-4 index was significantly associ- ated with all-cause mortality (p = 0.030) (Table 1). In comparison, among 113 age-, sex-, race-matched control ED patients who did not have HCV infection, 3 died within one year after their ED encounter, [i.e. mortality: 26.5 per 1000 PYs, mortality rate ratio for HCV positive vs negative: 3.33 (95%CI: 0.94, 11.79)].

Regarding ED obtained FIB-4 scores, characterization of liver fibrosis staging in this group of patients by imaging was as follows. Among 27 patients in whom we obtained transient elastography results, 8 (29.6%) had advanced fibrosis by imaging, and 19 did not. Of those 8 pa- tients 6/8 (75%) had FIB-4 scores N 3.25. Of those remaining 19 patients without advanced fibrosis, 15/19 (79%) had FIB-4 scores <= 3.25.

1. Discussion

In this study, among persons with chronic hepatitis C attending an urban ED, we found a high prevalence of patients with advanced liver disease using a non-invasive blood-based serum fibrosis index that was available to the providers during the ED visit for this group of pa- tients. That finding coupled with the demonstrated incomplete high rates of linkage to curative care services and very high mortality among those with advanced liver disease, suggests that liver disease staging at the time of the ED visit could be used to prioritize LTC services for patients in the ED. Multiple factors including loss to follow-up, pa- tient deference of treatment due to comorbidities, and treatment denial by the insurer were some of the key determinants for the majority of pa- tients who were linked to care but did not receive HCV treatment, in spite of the fact that HCV is now a curable infection. These findings un- derscore the importance of the need to improve systems for linking ED patients with chronic hepatitis C into care, to include using readily avail- able risk of progression information and education to help prioritize what are now scarce resources for achieving HCV cures for those pa- tients with advanced liver fibrosis.

To the best of our knowledge, this is one of the first ED LTC programs

for previously diagnosed HCV-infected patients in the nation. In an ED where we have a prevalence of chronic HCV of 12% (which equals to several thousand individual ED patients per year, in just a single ED), significant gains could be realized by advancing efforts to better link those with previously diagnosed HCV, including initiation of antiviral treatment, clearing HCV, and reducing the pool of HCV in the commu- nity. Finding from our ED compare favorably to composite reported

Fig. 1. HCV care continuum in 113 chronic HCV-infected emergency department patients by advanced liver fibrosis status which was estimated by FIB-4 index. Footnote: 1 ED patient was excluded from the final analysis due to incomplete data, leaving n = 113.

outcomes from two other U.S. urban ED HCV screening programs [12], with: higher rates of interest in LTC services (94% versus 52%); similar actual LTC rates (34% versus 32%); slightly higher rate of treatment ini- tiation (14% versus 8%); and double the rates of sustained viral response, SVR4 (12% versus 6%).

A major gap in the HCV care continuum observed in this group of pa- tients is attendance at an initial LTC visit, which we believe could be di- rectly related to shortfalls in the current approaches being used for communicating both the urgency and necessity of receiving HCV care - from both the patient and the downstream provider/system perspec- tives. Patients might have limited knowledge or misconception regard- ing HCV, due to a variety of factors including the slow and indolent nature of the disease, lingering perceptions of the lack of effective treat- ment options (rooted in communities historical experience with inter- feron therapy), and perceptions of HCV having a relatively low morbidity and mortality (relative to other infectious disease condition such as HIV). To mitigate these challenges, we are proposing use of a simple risk stratification tool which could be deployed in real-time in the ED and reliably predict clinical outcomes at the time of the ED en- counter (such as FIB-4 or point-of-care transient elastography). Imple- mentation of such as tool could represent a paradigm shift in that it would provide critical information to both patients and providers (as well as systems) and potentially impact the timeliness of engagement in care, and other key steps along the HCV care continuum.

The current nationwide shortage of an adequate specialist workforce for caring and treating for the almost 3 million Americans with chronic HCV infection [21], is recognized to contribute to national trends of long wait time for patients with chronic HCV infection, to be first seen by a trained specialist. Although this is not the case at our institution, the issue of under-capacity for HCV care is particularly palpable for patients and providers who work in urban ED settings, where the burden of dis- ease is especially high. The median wait time reported from EDs in Oak- land, California and Birmingham, Alabama was at least 5 months [12]. Despite the relatively small number of patients evaluated in this pilot study (and the fact that we work in a system where HCV specialty care exists ‘in house’), our preliminary findings highlight the potential adverse impact of delayed HCV care among those with advanced fibro- sis; b50% of those linked to care; only 41% of those linked receiving treatment within 1 year; 60% of those linked have treatment deferred, due to comorbidity and/or severe liver diseases (50% of them deceased). Integration of an FIB-4 calculator into the EMR and incorporating that tool into the routine process of patient care for those with chronic HCV infection is a feasible approach and would permit rapid assessment of fibrosis severity. Similar approaches has been demonstrated in the ED setting for patients in need of other ‘risk stratified services’ such as pal- liative care, with favorable outcomes [22,23]. Downstream outcomes for those with untreated HCV could be significant, given current published LTC rates (~32%) for HCV-infected patients identified in the ED [12]. The integration of a rapid, non-invasive index such as the FIB-4 could allow for the assessment and prioritization of patients with advanced fibrosis for connection to resources and LTC while they are still receiving care in the ED. Thus, LTC rate among ED HCV-infected patients will be signifi- cantly improved as well as the downstream stages of the HCV Care Continuum.

In the determination of fibrosis severity, the liver biopsy is tradition- ally considered the “gold standard”. Non-invasive tests, however, are a more suitable alternative for monitoring Disease progression and are not subject to sampling error and intra/inter-observer variability [24]. Among non-invasive tests, transient elastography (FibroScan) has been used to obtain a liver stiffness measurement. A simpler and cheaper alternative, the FIB-4 index was advanced about a decade ago, and advocated for use based on reliability as well as wide-spread avail- ability using values from a patient’s comprehensive metabolic panel [13,14]. Consistent with the findings in the literature [25-27], the FIB- 4 index measurements here were highly correlated with FibroScan re- sults and correctly identified patients with advanced fibrosis in our

ED. Notably, in our state Maryland, even though Medicaid provides HCV antiviral treatment coverage to participants with the fibrosis stage of F2 or higher that is determined by liver elastography (FibroScan(R)) or the commercially available blood index known as HCV FibroSure(TM) [28], we suggest that FIB-4 would provide a highly practical tool that can be used to prioritize initial referral for services, and once linked to care, additional staging tests could be performed as required for approval of initiation of medical treatment.

Our prevalence of advanced fibrosis (34%) was similar to that ob- served in another cohort of patients in care for chronic hepatitis C drawn from patients who had medical care provided in one of 4 large in- tegrated healthcare systems in U.S. [14], but was much higher than the 13% with chronic HCV infection, which reported in the general U.S. pop- ulation [29]. Notably, our all-cause mortality rate was approximately 2.5 to 4 times higher than that reported by two cohorts of chronic HCV- infected individuals [14,30], and 10 times higher than that in the general

U.S. population [31]. Furthermore, relative to our general ED population, the all-cause mortality rate was 3.3 times higher for those with previ- ously diagnosed HCV infection, matching for age, sex and race. Opportu- nities for interventions along each stage of the HCV care continuum including linkage to care, initiation of antiviral treatment, adherence to treatment, would most likely decrease both the HCV-related, and all-cause mortality.

Generalizability is the most significant limitation of our study. Our long-standing ED-based HIV program made it easier for the staff in our ED to adapt to the HCV LTC process with the affiliated viral hepatitis clinic. It is possible that our successful LTC might not be reproducible in other resource-limited EDs, such as in the low-income rural setting or a setting which lacks nearby and engaged partners for LTC. In addition, this study was limited by the data available in the EMR. For example, when the FIB-4 was calculated, the values which were drawn from the EMR included current (and if not available), as well as most recent up to the six months prior to date of the encounter. It is possible that these values, such as platelet count, AST, and ALT, could have changed during this time. Additionally, chart review one-year after the index visit, may not have provided a comprehensive picture of the patient’s HCV care continuum measures, as patient information may not be fully captured based on their encounters within our health system; however the vast majority of patients who visit the JHHED use our health system as their primary care site. Moreover, selection bias may have occurred such that the patients we studied may not be fully repre- sentative of all those with chronic HCV in the ED - we enrolled a conve- nience sample including only those for whom the patient-care navigator was present. We estimated that up to 4500 unique ED pa- tients could have chronic HCV infection during the 8-month study pe- riod or approximately 1000 patients with chronic HCV infection, were a full-time linkage to care staff was in place (and were every HCV in- fected patient been previously tested with documentation of their re- sults in the chart) [7]. Of note, many of those individuals would not able to be included in the program due to varied factors including but not limited to lack of documentation of their current serostatus, high acuity of illness and/or altered mental status during their ED stay, in ad- dition to the lack of 24/7 availability of LTC staff. Nevertheless, this is a small convenience sample, we found that there was no significant dif- ference with regard to age, gender, and race between enrollees and those who had chronic HCV infection using data from the 2013 sero- prevalence study conducted in the same ED [7]. Another limitation of this study is that we used SVR4 instead of SVR12 to measure the treat- ment success for patients who received HCV treatment, given the antic- ipated challenges with follow-up from an urban ED population. However, the bias is likely limited since the extremely high concordance between SVR4 and SVR12 with a positive predictive value of 98% and a negative predictive value of 100% [19]. Finally, HCV medication for those who did not have advanced liver fibrosis (F0 - F2) by the standard stag- ing method was limited in our state since they were not eligible for treatment by the State of Maryland Medicaid guidelines.

Declaration of interests”>In summary, we found a high prevalence of advanced liver fibrosis as measured by FIB-4 index, as well as a high mortality rate among pa- tients with chronic HCV infection in our ED. Given the substantial bur- den of HCV-related illness in urban ED patients nationally, and the recognized fact that EDs are the often the only point of contact with the health care system for many of these patients, we propose incorpo- rating FIB-4 based rapid assessment into ED-based HCV screening and LTC programs in order to prioritize LTC for patients with advanced liver fibrosis, as well as routine ED clinical practice. Increasing both pro- vider and patient awareness of the value of liver fibrosis staging could also serve to motivate patients with advanced liver disease to attend scheduled LTC services and yield improvements in downstream HCV care continuum outcomes.

Contributors

Y-HH designed the study. DS, AVP, VV, and MSS had primary respon- sibility for the data collection. Y-HH performed data analyses. YH-H, DS, RER, RI, MSS, and DLT primarily interpreted results. YH-H, AVP, and VV primarily drafted the manuscript. RER, MS, RI, MSS, and DLT performed critical editing of the manuscript.

Declaration of interests

We declare no competing interests.

Funding

This work was supported by the National Institute on Drug Abuse (R37DA013806 to D. L. T.) at the National Institutes of Health, and the Gilead Sciences, Inc.’s HIV FOCUS program. Dr. Hsieh is also supported in part by a National Institutes of Health award, K01AI100681 from Na- tional Institute of Allergy and Infectious Diseases.

Ethics committee approval

A quality improvement evaluation of an ED-based HCV LTC program received an approval from The Johns Hopkins University School of Med- icine Institutional Review Board. The Johns Hopkins University School of Medicine Institutional Review Board approved the identity-unlinked se- roprevalence study.

References

1. Denniston M, Jiles R, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014;160(5):293-300.
2. Division of Viral Hepatitis CfDCaPC. Viral Hepatitis - Statistics & Surveillance. Avail- able at: http://www.cdc.gov/hepatitis/statistics/, Accessed date: 7 June 2016.
3. Ly K, Xing J, Klevens R, Jiles R, Ward J, Holmberg S. The increasing burden of mortal- ity from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012;156(4):271-8.
4. Kelen G, Green G, Purcell R, et al. Hepatitis B and hepatitis C in emergency depart- ment patients. N Engl J Med 1992;326(21):1399-404.
5. Bansal J, Constantine N, Zhang X, Callahan J, Wasserman S, Marsiglia V. Multiple blood-borne and sexually transmitted infections in sexually transmitted disease clinic and hospital emergency room patient populations. Sex Transm Dis 1993;20 (4):220-6.
6. Brillman J, Crandall C, Florence C, Jacobs J. prevalence and risk factors associated with hepatitis C in ED patients. Am J Emerg Med 2002;20(5):476-80.
7. Hsieh Y, Rothman R, Laeyendecker O, et al. Evaluation of the centers for disease con- trol and prevention recommendations for hepatitis C virus testing in an urban emer- gency department. Clin Infect Dis 2016;62(9):1059-65.
8. Galbraith J, Donnelly J, Franco R, Overton E, Rodgers J, Wang H. National estimates of healthcare utilization by individuals with hepatitis C virus infection in the United States. Clin Infect Dis 2014;59(6):755-64.
9. Morrill J, Shrestha M, Grant R. Barriers to the treatment of hepatitis C: patient, pro- vider, and system factors. J Gen Intern Med 2005;20(8):754-8.
10. Sebastiani G, Gkouvatsos K, Pantopoulos K. Chronic hepatitis C and liver fibrosis. World J Gastroenterol 2014;20(32):11033-53.
11. Franco R, Overton E, Tamhane A, et al. Characterizing failure to establish hepatitis c care of Baby boomers diagnosed in the emergency department. Open Forum Infect Dis 2016;3(4):ofw211.
12. Anderson E, Galbraith J, Deering L, et al. Continuum of care for HCV among patients diagnosed in the emergency department setting. Clin Infect Dis 2017;64(11): 1540-6.
13. Vallet-Pichard A, Mallet V, Pol S. FIB-4: a simple, inexpensive and accurate marker of

fibrosis in HCV-infected patients. Hepatology 2006;44(3):769.

1. Holmberg S, Lu M, Rupp L, et al. Noninvasive serum fibrosis markers for screening and staging chronic hepatitis C virus patients in a large US cohort. Clin Infect Dis 2013;57(2):240-6.
2. Harrison S. Utilization of FibroScan testing in hepatitis C virus management. Gastroenterol Hepatol 2015;11(3):187-9.
3. Poynard T, Imbert-Bismut F, Munteanu M, Ratziu V. FibroTest-FibroSURE: towards a universal biomarker of liver fibrosis? Expert Rev Mol Diagn 2005;5(1):15-21.
4. Burgess S, Hussaini T, Yoshida E. Concordance of sustained virologic response at weeks 4, 12 and 24 post-treatment of hepatitis c in the era of new oral direct- acting antivirals: a concise review. Ann Hepatol 2016;15(2):154-9.
5. Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 2013;144(7):1450-5.e2.
6. Yoshida E, Sulkowski M, Gane E, et al. Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepa- titis C virus. Hepatology 2015;61(1):41-5.
7. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128(2):343-50.
8. Kattakuzhy S, Wilson E, Sidharthan S, et al. Moderate sustained virologic response rates with 6-week combination directly acting anti-hepatitis C virus therapy in pa- tients with advanced liver disease. Clin Infect Dis 2016;62(4):440-7.
9. Liberman T, Kozikowski A, Kwon N, Emmert B, Akerman M, Pekmezaris R. Identify- ing advanced illness patients in the emergency department and having goals-of-care discussions to assist with early hospice referral. J Emerg Med 2018;54(3):191-7.
10. Bowman J, George N, Barrett N, Anderson K, Dove-Maguire K, Baird J. Acceptability and reliability of a novel palliative care screening tool among emergency depart- ment providers. Acad Emerg Med 2016;23(6):694-702.
11. Regev A, Berho M, Jeffers L, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97(10): 2614-8.
12. Cepeda J, Solomon S, Srikrishnan A, et al. Serum fibrosis markers for the diagnosis of liver disease among people with chronic hepatitis C in Chennai, India. Open Forum Infect Dis 2016;23(3):ofw156.
13. Nguyen Truong T, Laureillard D, Lacombe K, et al. High proportion of HIV-HCV coinfected patients with advanced liver fibrosis requiring hepatitis C treatment in Haiphong, Northern Vietnam (ANRS 12262). PLoS One 2016;11(5):e0153744.
14. Mehta S, Buckle G. Assessment of liver disease (noninvasive methods). Curr Opin HIV AIDS 2011;6(6):465-71.
15. Maryland Deparment of Health. Joint Chairmen’s Report on Hepatitis C Treat- ment. Available at: https://mmcp.health.maryland.gov/Documents/JCRs/2017/ hepcJCRfinal10-17.pdf, Accessed date: 8 May 2018.
16. Xu F, Leidner A, Tong X, Holmberg S. Estimating the number of patients infected with chronic HCV in the United States who meet highest or high-priority treatment criteria. Am J Public Health 2015;105(7):1285-9.
17. Emmanuel B, Shardell M, Tracy L, Kottilil S, El-Kamary S. Racial disparity in all-cause mortality among hepatitis C virus-infected individuals in a general US population, NHANES III. J Viral Hepat 2017;24(5):380-8.
18. National Center for Health Statistics. Deaths and Mortality. Available at: https:// www.cdc.gov/nchs/fastats/deaths.htm, Accessed date: 16 March 2017.