RESUMEN
Interferon-free DAA therapies have recently been licensed for patients infected with hepatitis C virus (HCV) who have decompensated cirrhosis (DC). Our aim was to describe factors associated with uptake of IFN-free DAAs in DC patients and to compare mortality risk and hospital admission rates between pre-DAA and DAA eras. This observational study used record-linkage between Scotland's HCV Clinical Database and national inpatient hospitalization and mortality registers. For the DAA uptake analysis, the study population (n = 297) was restricted to patients alive on 1 November 2014, and Cox regression was used to estimate uptake associated with various covariates. For the Cox regression of mortality comparing pre-DAA and DAA eras, the study population (n = 624) comprised those diagnosed with DC in 2005-2018; follow-up was censored at two years. DAA uptake was 63% overall and was significantly higher for treatment-experienced patients (adjusted hazard ratio (aHR) = 1.64, 95% CI:1.14-2.34), genotype 1 vs. other genotypes (aHR = 1.55. 95% CI:1.15-2.10) and lower for persons diagnosed with DC pre-2014 (0.47, 95% CI:0.33-0.68) and in Greater Glasgow (0.64, 95% CI:0.47-0.88). The intention-to-treat SVR rate was 89% (95% CI:83-93%). All-cause and liver-related mortality risk were significantly reduced among patients diagnosed with DC in the DAA era (November 2014-December 2018) compared with the pre-DAA era (2005-October 2014) (aHRs of 0.68, 95% CI:0.49-0.93; 0.69, 95% CI:0.50-0.95, respectively); in contrast, hospital admission rates were higher in the DAA era (aRR = 1.14, 95% CI:1.04-1.26). The majority of HCV-infected DC patients engaged with specialist services can be treated with IFN-free DAAs. Improved survival among patients diagnosed with DC in the DAA era supports the beneficial impact of IFN-free therapies among those with advanced liver disease.
Asunto(s)
Hepatitis C Crónica , Hepatitis C , Antivirales/uso terapéutico , Hepacivirus , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Cirrosis Hepática/tratamiento farmacológicoRESUMEN
Few studies have investigated clinical outcomes among patients with cirrhosis who were treated with interferon (IFN)-free direct-acting antiviral (DAA). We aimed to quantify treatment impact on first decompensated cirrhosis hospital admission, first hepatocellular carcinoma (HCC) admission, liver-related mortality and all-cause mortality among a national cohort of cirrhotic patients. Through record linkage between Scotland's HCV Clinical Database and inpatient/day-case hospitalization and deaths records, a study population comprising chronic HCV-infected patients with compensated cirrhosis and initiated on IFN-free DAA between 1 March 2013 and 31 March 2018 was analysed. Cox regression evaluated the association of each clinical outcome with time-dependent treatment status (on treatment, responder, nonresponder or noncompliant), adjusting for patient factors including Child-Pugh class. Among the study population (n = 1073) involving 1809 years of follow-up, 75 (7.0%) died (39 from liver-related causes), 47 progressed to decompensated cirrhosis, and 28 developed HCC. Compared with nonresponders, treatment response (96% among those attending their 12 weeks post-treatment SVR test) was associated with a reduced relative risk of decompensated cirrhosis (hazard ratio [HR] = 0.14; 95% CI: 0.05-0.39), HCC (HR = 0.17; 95% CI: 0.04-0.79), liver-related death (HR = 0.13; 95% CI: 0.05-0.34) and all-cause mortality (HR = 0.30; 95% CI: 0.12-0.76). Compared with responders, noncompliant patients had an increased risk of liver-related (HR = 6.73; 95% CI: 2.99-15.1) and all-cause (HR = 5.45; 95% CI: 3.07-9.68) mortality. For HCV patients with cirrhosis, a treatment response was associated with a lower risk of severe liver complications and improved survival. Our findings suggest additional effort is warranted to address the higher mortality among the minority of cirrhotic patients who do not comply with DAA treatment or associated RNA testing.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/complicaciones , Cirrosis Hepática/complicaciones , Cirrosis Hepática/mortalidad , Adulto , Carcinoma Hepatocelular/epidemiología , Estudios de Cohortes , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Humanos , Incidencia , Interferones/uso terapéutico , Hígado/patología , Hígado/virología , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Escocia/epidemiología , Respuesta Virológica SostenidaRESUMEN
BACKGROUND: Primary measures for preventing morbidity and mortality associated with bleeding gastroesophageal varices in cirrhotic patients include endoscopic screening. AIM: To identify factors associated with (a) screening and (b) first hospital admission for variceal bleeding among cirrhotic hepatitis C virus (HCV) patients attending specialist care in Scotland. METHODS: The Scottish Hepatitis C Clinical Database was linked to national hospitalisation and deaths records to identify all chronic HCV patients diagnosed with compensated cirrhosis in 2005-2016 (n = 2741). The adjusted odds of being screened by calendar year period were estimated using logistic regression, and the adjusted hazard ratio (HR) of a first variceal bleed using Cox regression. RESULTS: About 34% were screened within the period starting 12 months before and ending 12 months after cirrhosis diagnosis. The proportion screened was stable in 2005-2010 at 42%, declining to 37% in 2011-2013 and 26% in 2014-2016. Odds of screening were decreased for age-groups <40 (OR = 0.61, 95% CI: 0.48-0.77) and 60+ years (OR = 0.67, 95% CI: 0.48-0.94), history of antiviral therapy (OR = 0.70, 95% CI: 0.55-0.89), and cirrhosis diagnosis in 2014-2015, compared with 2008-2010 (OR = 0.67, 95% CI: 0.52-0.86). Compared with 2008-2010, there was no evidence for an increased/decreased relative risk of a first variceal bleed in any other period, but viral clearance was associated with a lower risk (HR = 0.56, 95% CI: 0.32-0.97). CONCLUSIONS: Overall screening uptake following cirrhosis diagnosis was low, and the decline in recent years is of concern. The stable bleeding risk over time may be attributable both to ongoing prevention initiatives and to changing diagnostic procedures creating a patient pool with milder disease in more recent years.
Asunto(s)
Endoscopía Gastrointestinal/estadística & datos numéricos , Várices Esofágicas y Gástricas/diagnóstico , Hemorragia Gastrointestinal/etiología , Hepatitis C Crónica , Cirrosis Hepática , Participación del Paciente/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Bases de Datos Factuales , Certificado de Defunción , Várices Esofágicas y Gástricas/complicaciones , Várices Esofágicas y Gástricas/epidemiología , Femenino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/epidemiología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/epidemiología , Humanos , Almacenamiento y Recuperación de la Información , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Masculino , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Factores de Riesgo , Escocia/epidemiología , Análisis de SupervivenciaRESUMEN
BACKGROUND & AIMS: To describe the burden on inpatient hospital resources over time from patients diagnosed with hepatitis C virus (HCV) infection and who have reached the decompensated stage of cirrhosis (DC), as existing estimates of hospital stay in these patients are limited. METHODS: A retrospective longitudinal dataset was formed via record-linkage between the national HCV diagnosis database and inpatient/daycase hospitalisation and death registers in Scotland. The study population consisted of HCV-diagnosed patients with a first DC admission in 1996-2013, with follow-up available until 31 May 2014. We investigated and quantified the mean cumulative length of hospital stay, distributions over discharge diagnosis categories, and trends in admission rates. RESULTS: Among our study population (n = 1543), we identified 10 179 admissions with any diagnosis post-first DC admission. Between 1996 and 2013 there was a 16-fold rise in annual total admissions (from 112 to 1791) and an 11-fold rise in hospital stay (719-8045). When restricting minimum possible follow-up to 2 years, DC patients (n = 1312) had an overall admission rate of 7.3 per person-year, and spent on average 43 days (26 days during first 6 months) in hospital; for all liver-related, liver-related other than HCC/DC, and non-liver related only admissions, this was 39, 14, and 5 days respectively. CONCLUSIONS: HCV-infected DC patients impose a considerable inpatient hospital burden, mostly from DC- and other liver-related admissions, but also from admissions associated with non-liver comorbidities. Estimates will be useful for monitoring the impact of prevention and treatment, and for computing the cost-effectiveness of new therapies.
Asunto(s)
Costo de Enfermedad , Hepatitis C Crónica/complicaciones , Pacientes Internos/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Cirrosis Hepática/epidemiología , Adulto , Anciano , Análisis Costo-Beneficio , Bases de Datos Factuales , Femenino , Hepacivirus/genética , Hepatitis C Crónica/epidemiología , Humanos , Cirrosis Hepática/terapia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Escocia/epidemiologíaRESUMEN
Seven years have elapsed since the Scottish Government launched its Hepatitis C Action Plan - a Plan to improve services to prevent transmission of infection, particularly among people who inject drugs (PWID), identify those infected and ensure those infected receive optimal treatment. The Plan was underpinned by industrial scale funding (around £100 million, in addition to the general NHS funding, will have been invested by 2015), and a web of accountable national and local multi-disciplinary multi-agency networks responsible for the planning, development and delivery of services. Initiatives ranged from the introduction of testing in specialist drug services through finger-prick blood sampling by non-clinical staff, to the setting of government targets to ensure rapid scale-up of antiviral therapy. The Plan was informed by comprehensive national monitoring systems, indicating the extent of the problem not just in terms of numbers infected, diagnosed and treated but also the more penetrative data on the number advancing to end-stage liver disease and death, and also through compelling modelling work demonstrating the potential beneficial impact of scaling-up therapy and the mounting cost of not acting. Achievements include around 50% increase in the proportion of the infected population diagnosed (38% to 55%); a sustained near two-and-a-half fold increase in the annual number of people initiated onto therapy (470 to 1050) with more pronounced increases among PWID (300 to 840) and prisoners (20 to 140); and reversing of an upward trend in the overall number of people living with chronic infection. The Action Plan has demonstrated that a Government-backed, coordinated and invested approach can transform services and rapidly improve the lives of thousands. Cited as "an impressive example of a national strategy" by the Global Commission on Drug Policy, the Scottish Plan has also provided fundamental insights of international relevance into the management of HCV among PWID.
Asunto(s)
Política de Salud/legislación & jurisprudencia , Accesibilidad a los Servicios de Salud/legislación & jurisprudencia , Hepatitis C/terapia , Abuso de Sustancias por Vía Intravenosa/terapia , Investigación Biomédica , Hepatitis C/tratamiento farmacológico , Hepatitis C/etiología , Humanos , Escocia , Abuso de Sustancias por Vía Intravenosa/complicacionesRESUMEN
UNLABELLED: Sustained viral response (SVR) is the optimal outcome of hepatitis C virus (HCV) therapy, yet more detailed data are required to confirm its clinical value. Individuals receiving treatment in 1996-2011 were identified using the Scottish HCV clinical database. We sourced data on 10 clinical events: liver, nonliver, and all-cause mortality; first hospitalisation for severe liver morbidity (SLM); cardiovascular disease (CVD); respiratory disorders; neoplasms; alcohol-intoxication; drug intoxication; and violence-related injury (note: the latter three events were selected a priori to gauge ongoing chaotic lifestyle behaviours). We determined the association between SVR attainment and each outcome event, in terms of the relative hazard reduction and absolute risk reduction (ARR). We tested for an interaction between SVR and liver disease severity (mild vs. nonmild), defining mild disease as an aspartate aminotransferase-to-platelet ratio index (APRI) <0.7. Our cohort comprised 3,385 patients (mean age: 41.6 years), followed-up for a median 5.3 years (interquartile range: 3.3-8.2). SVR was associated with a reduced risk of liver mortality (adjusted hazard ratio [AHR]: 0.24; P < 0.001), nonliver mortality (AHR, 0.68; P = 0.026), all-cause mortality (AHR, 0.49; P < 0.001), SLM (AHR, 0.21; P < 0.001), CVD (AHR, 0.70; P = 0.001), alcohol intoxication (AHR, 0.52; P = 0.003), and violence-related injury (AHR, 0.51; P = 0.002). After 7.5 years, SVR was associated with significant ARRs for liver mortality, all-cause mortality, SLM, and CVD (each 3.0%-4.7%). However, we detected a strong interaction, in that ARRs were considerably higher for individuals with nonmild disease than for individuals with mild disease. CONCLUSIONS: The conclusions are 3-fold: (1) Overall, SVR is associated with reduced hazard for a range of hepatic and nonhepatic events; (2) an association between SVR and behavioral events is consistent with SVR patients leading healthier lives; and (3) the short-term value of SVR is greatest for those with nonmild disease.
Asunto(s)
Causas de Muerte , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/mortalidad , Cirrosis Hepática/virología , Fallo Hepático/virología , Adulto , Anciano , Antivirales/uso terapéutico , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Hepatitis C Crónica/fisiopatología , Humanos , Cirrosis Hepática/mortalidad , Cirrosis Hepática/fisiopatología , Fallo Hepático/mortalidad , Fallo Hepático/fisiopatología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Conducta de Reducción del Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: The global burden associated with hepatitis C virus (HCV) infection has prompted a scale-up of antiviral therapy. Hitherto, no data exist on the impact of scaling-up, on the characteristics of treated populations, or on sustained viral response (SVR) rates. We assessed the country-wide scale-up of antiviral therapy in Scotland, a country which nationally monitors uptake of and response to HCV treatment. METHODS: Data for patients, initiated on combined pegylated interferon and ribavirin therapy at 13 specialist HCV clinics in 2001-2010, were extracted from the Scottish HCV Clinical Database (n=3895). Patient characteristics included age, genotype, PWID (people who inject drugs) status, prison referral, and diagnosed cirrhosis. Temporal trends in covariates and adjusted effects on a SVR were examined via mixed-effects regression. RESULTS: The number of patients starting treatment increased from 237 in 2001-2002 to 1560 in 2009-2010, with an increasing trend in SVR from 44% to 57% over this period. For a given clinic, between 2001/2 and 2010 there was a decrease in the odds of those treated being diagnosed with cirrhosis (odds ratio [OR]=0.84 per year), and increasing temporal trends for those treated being PWID (OR=1.08) and prison referrals (OR=1.06). Adjusting for covariates, the proportion of a given clinic's patients achieving SVR was positively associated with the percentage of PWID (OR=1.01 per percent increase; 95% confidence interval [CI]: 1.00-1.02) and genotype 2/3 (OR=1.03; 95% CI: 1.02-1.04). CONCLUSIONS: Despite changes in patient characteristics, a country-wide scale-up of antiviral therapy did not compromise SVR rates. Results are highly relevant to countries planning on scaling-up treatment, given the forthcoming availability of new interferon-free therapies.
Asunto(s)
Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , ARN Viral/genética , Ribavirina/uso terapéutico , Adulto , Antivirales/uso terapéutico , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Genotipo , Hepatitis C Crónica/virología , Humanos , Masculino , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Carga ViralRESUMEN
UNLABELLED: A substantial baseline risk of liver cirrhosis exists for patients with chronic hepatitis C virus (HCV) infection. However, the extent to which this could be driven by heavy alcohol use is unclear. Therefore, our principal aim was to determine the fraction of cirrhosis attributable to heavy alcohol use among chronic HCV patients attending a liver clinic. The study population comprised chronic HCV patients who had attended one of five liver clinics in Scotland during 1996-2010 and had (1) remained in follow-up for at least 6 months, (2) acquired HCV through either injecting drugs or blood transfusion, and (3) an estimated date of acquiring infection. Predictors of cirrhosis were determined from multivariate logistic regression. Regression parameters were used to determine the fraction of cirrhosis attributable to heavy alcohol use. Among 1,620 patients, 9% were diagnosed with cirrhosis, and 34% had ever engaged in heavy alcohol use (>50 units/week for a sustained period). Significant predictors of cirrhosis were age, duration of infection, and ever heavy alcohol use. The fraction of cirrhosis attributable to ever heavy alcohol use was 36.1% (95% confidence interval [CI]: 24.4-47.4). Moreover, among patients who had ever engaged in heavy alcohol use specifically, this attributable fraction exceeded 50% (61.6%; 95% CI: 47.0-72.2). CONCLUSIONS: A substantial proportion of patients with chronic HCV develop liver cirrhosis as a consequence of heavy alcohol use. This has not been adequately acknowledged by cost utility analyses (CUAs). As such, estimates of cost-effectiveness may be exaggerated. Thus, these data are important to guide forthcoming CUAs in terms of taking better account of the factors leading to cirrhosis among patients with chronic HCV.
Asunto(s)
Hepatitis C Crónica/complicaciones , Cirrosis Hepática Alcohólica/etiología , Cirrosis Hepática/virología , Adulto , Alcoholismo/complicaciones , Análisis Costo-Beneficio , Progresión de la Enfermedad , Femenino , Hepatitis C Crónica/economía , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/economía , Cirrosis Hepática/epidemiología , Cirrosis Hepática Alcohólica/economía , Masculino , Persona de Mediana Edad , Escocia/epidemiologíaRESUMEN
BACKGROUND: Unsafe injecting practices put injecting drug users (IDUs) at repeat exposure to infection with the hepatitis C virus (HCV). It has not yet been determined if spontaneously clearing one's primary infection influences the risk of reinfection; our aim was to estimate the relative risk of reinfection in IDUs who have cleared the virus. METHODS: We conducted a retrospective study using a large database of HCV test results covering Greater Glasgow Health Board during 1993-2007 to calculate rates of infection and reinfection in current/former IDUs. The relative risk of (re)infection in previously infected compared with never-infected IDUs was estimated using Poisson regression, adjusting for age at study entry, sex, and calendar period of test. RESULTS: Although the rate of reinfection in IDUs who were HCV antibody-positive, RNA-negative at baseline was lower (7/100 person-years, 95% CI: 5-9) than the rate of acute infection in IDUs who were HCV antibody-negative at baseline (10/100 person-years, 95% CI: 9-12), the risk of reinfection was not significantly different than the risk of initial infection (adjusted rate ratio=0.78, 95% CI: 0.57-1.08). CONCLUSION: We found only weak evidence for a reduced risk of HCV reinfection in IDUs who had cleared their previous infection. Further research among those who have cleared infection through antiviral therapy is needed to help inform decisions regarding treatment of IDUs.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C/epidemiología , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto , Bases de Datos Factuales , Femenino , Hepacivirus/inmunología , Hepatitis C/tratamiento farmacológico , Humanos , Incidencia , Masculino , Distribución de Poisson , ARN Viral/sangre , Recurrencia , Análisis de Regresión , Estudios Retrospectivos , Riesgo , Escocia/epidemiología , Adulto JovenRESUMEN
OBJECTIVES: From the literature on the hepatitis C virus, the existence of a gap between a sustained virologic response (SVR) attainable in randomized clinical trials (RCTs) versus routine practice is not clear. Further, in terms of the pretreatment prediction of SVR, to date, studies have focused only on reporting the magnitude of association (MOA) between each predictor and an SVR. They fail to acknowledge that a predictor with a large MOA is of little value to clinicians if it has low variability in the treatment population. METHODS: Hepatitis C virus clinical databases were used to derive a large, representative cohort of Scottish pegylated interferon and ribavirin initiates. RESULTS: Overall, 39% [123/315, 95% confidence interval (CI) 34-45%] of genotype 1 and 70% (414/594, 95% CI 66-73%) of genotype 2/3 patients achieved an SVR; this compares with the pooled estimates of 47% for genotype 1 (95% CI 41-52%) and 80% for genotype 2/3 (95% CI 75-85%) RCT participants. Significant predictors of SVR identified from logistic regression were ranked on the basis of the akaike information criteria (reflecting an approach that will account for each predictor's MOA and variability) as follows: (i) genotype, % increase in akaike information criteria of the final model when variables are excluded, 58.49%; (ii) γ-glutamyl transferase, 18.64%; (iii) platelet count, 6.48%; (iv) alanine aminotransferase quotient, 4.63%; (v) ever infected with hepatitis B virus, 4.31% and (vi) sex, 3.10%. CONCLUSION: (i) The proportion of patients attaining an SVR in Scottish routine practice is marginally lower than in RCTs and (ii) other than genotype, γ-glutamyl transferase emerges as a valuable predictor of an SVR in routine practice. Further, we demonstrate an approach to more clearly discern the predictive value of response predictors.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Aciltransferasas/sangre , Adulto , Distribución por Edad , Alanina Transaminasa/sangre , Biomarcadores/sangre , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepatitis C Crónica/sangre , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Pronóstico , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Distribución por Sexo , Resultado del TratamientoRESUMEN
UNLABELLED: Our objective was to address two shortfalls in the hepatitis C virus (HCV) literature: (1) Few data exist comparing post-treatment liver-related mortality/morbidity in HCV-sustained virologic response (SVR) patients to non-SVR patients and (2) no data exist examining liver-related morbidity among treatment response subgroups,particularly among noncirrhotic SVR patients, a group who in the main are discharged from care without further follow-up. A retrospective cohort of 1,215 previously naïve HCV interferon patients (treated 1996-2007)was derived using HCV clinical databases from nine Scottish clinics. Patients were followed up post-treatment for a mean of 5.3 years. (1) By Cox-regression, liver-related hospital episodes (adjusted hazard ratio [AHR]:0.22; 95% confidence interval [CI]: 0.15-0.34) and liver-related mortality [corrected] (AHR: 0.22; 95% CI: 0.09-0.58)were significantly lower in SVR patients, compared to non-SVR patients. (2) Rates of liver-related hospitalization were elevated among all treatment subgroups compared to the general population: Among noncirrhotic SVR patients, adjusted standardized morbidity ratio (SMBR) up to 5.9 (95% CI: 4.5-8.0); among all SVR patients,SMBR up to 10.5 (95% CI: 8.7-12.9); and among non-SVR patients, SMBR up to 53.2 (95% CI: 49.4-57.2).Considerable elevation was also noted among patients who have spontaneously resolved their HCV infection(a control group used to gauge the extent to which lifestyle factors, and not chronic HCV, can contribute toliver-related morbidity), SMBR up to 26.8 (95% CI: 25.3-28.3). CONCLUSIONS: (1) Patients achieving an SVR were more than four times less likely to be hospitalized, or die for a liver-related reason, than non-SVR patients and (2) although discharged, noncirrhotic SVR patients harbor a disproportionate burden of liver-related morbidity; up to six times that of the general population. Further, alarming levels of liver-related morbidity in spontaneous resolvers is an important finding warranting further study..