Health care quality and cost effectiveness


Effect of Lead Time Bias in the Evaluation of the Effectiveness of a Screening Program: Example of Screening by Ultrasound for Hepatocellular Carcinoma (HCC) in Compensated HCV-Related Cirrhosis

Abbas Mourad1,2, Michael Schwarzinger2, Nathalie Ganne-Carrie3, Isabelle Rosa4, Philippe Mathurin1, 5, Sylvie Deuffic-Burbon1,2

1Inserm U995, Université Lille Nord de France' LILLE, France; 2Inserm ATIP/Avenir, U738, Université paris Diderot,, PARIS' France; 3Service d, Hepato-Gastroentérologie, Hôpital Jean Verdier, BONDY, France; 4ANGH CHANGH Study Group, Centre Hospifolier Intercommunol, Créteil' France; 5Service Maladies de I'Apporeil digestif et de la Nufrifion, Hôpital Claude Huriez, LILLE, France

Background: Non-randomized controlled trials are confronted with lead time bias, i. e. an apparent improvement in survival due to anticipated diagnosis. We illustrated the effect of lead time bias by assessing the impact of ultrasonographic screening on survival of patients with compensated HCV-related HCC. Methods: We adapted a simple method of correction for lead time (LT) bias in survival analysis to HCC screening, estimating LT as Dtx3xlog(du/ds)/log(2), where Dt the median value of tumor volume doubling time, du and ds median tumor diameters of screened and unscreened patients, respectively. A Markov model was developed to simulate the progression of a cohort of patients with HCV-related HCC, aware of their HCV status, from diagnosis until death. Simulated patients were distributed and treated according to the tumor and health status at diagnosis. The model estimates life expectancy (LE) according to 3 scenarios: S1, no screening (du=4. 28cm); S2, current practice of screening corresponding to 42% of patients diagnosed at an early stage (ds=2. 8cm); S3, optimal practice of screening corresponding to 87% of patients diagnosed at an early stage (ds=2. 2cm). Estimates of du and ds were obtained from two French cohorts, CHANGH for current practice and CHし」000 for optimal practice of HCC screening. Estimate of Dt was found to be 117 days and was varied in sensitivity analysis assuming a less aggressive tumor (Dt=171 days). Estimates of Dt were obtained from studies evaluating growth rates of HCC. Results: A) Baseline analysis (Figure): Compared to no screening (S1), current practice of screening (S2) increases LE by 23 months without correcting for LT bias and by 19 months after correction, and optimal practice of screening (S3) increases LE by 53 months without correcting for LT bias and by 43 months after correction. B) Sensitivity analysis: When assuming a less aggressive tumor (Dt=171days vs. 117days), the LT bias would increase. Consequently, compared to no screening, LE with current practice of screening would decrease from 19 to 17 months, and LE with optimal practice of screening from 43 to 39 months. Conclusions: The benefit of HCC screening is overestimated when LT bias is not considered. Our approach allows quantifying the magnitude of LT bias and provides more accurate estimates of the benefit of HCC screening.



Nathalie Ganne-Carrie - Advisory Committees or Review Panels: Roche, MSD; Speaking and Teaching: BMS, Gilead

Philippe Mathurin - Board Membership: Schering-Plough, Janssen-Cilag, BMS, Gilead; Consulting: Roche, Bayer, Boehringer

Sylvie Deuffic-Burban - Consulting: MSD, GSK, Gilead, Abbott; Grant/Research Support: Roche, Janssen Pharmaceuticals, Schering-Plough; Speaking and Teaching: Cellestis

The following people have nothing to disclose: Abbas Mourad, Michael Schwarzinger, Isabelle Rosa


Non-invasive biomarkers unearth undiagnosed cirrhosis in the community

David J. Harman, Emilie A. Wilkes, Martin W. James, Stephen D. Ryder' Guruprosod F Aithal, Indro Neil Guha

Nottingham Digestive Diseases Biomedical Research Unit, University Of Nottingham, Nottingham, United Kingdom

Background and Aims: Liver cirrhosis prevalence and mortality continues to rise and diabetes and alcohol excess are the major risk factors contributing to the burden. Traditional liver biochemistry panels have a poor sensitivity and specificity for advanced liver disease; they are likely to miss a substantial proportion of patients with advanced fibrosis. Our aim was to investigate the feasibility of implementing a serial, non-invasive algorithm exclusively performed in a community setting and targeted upon risk factors to identify and stratify patients with chronic liver disease. Materials and Methods: The study was based in a community population of 12, 368 patients covered by two family practices. Patients with risk factors for developing chronic liver disease (hazardous alcohol use, type 2 diabetes or persistently raised alanine aminotransferase (ALT) but normal liver serology) were identified and invited to participate; those with known chronic liver disease were excluded. We used a two stage stratification algorithm. At first, we used an AST: ALT ratio of >/= 0.8 or BARD score>/= 2, simple tests with high negative predictive values, and those who were above the critical threshold were offered transient elastography using a portable probe (FS402). A liver stiffness of greater than 8 kilopascals (KPA) was defined as likely hepatic fibrosis and prompted referral for consultation with a visiting liver specialist within the community setting. Results: We identified 920 patients with the defined risk factors (314 type 2 diabetes and 627 hazardous alcohol, of whom 21 had dual risk factors); 504 patients agreed to undergo the first step blood biomarker. A normal AST: ALT ratio or BARD score was found in 62 patients (12. 3%) who required no further stratification. Subsequently, 378/442 patients (85. 5%) agreed to undergo transient elastography. Liver stiffness greater than 8KPA was found in 98 patients undergoing transient elastography (25. 9%). Importantly 71/98 (72. 4%) patients with elevated liver stiffness had normal liver enzymes. しsing this algorithm, 11 new patients with definite cirrhosis have been identified. The total identified practice cirrhotic population is now 19 patients which is equivalent to 153. 6 cases per 100, 000 population; double the expected population prevalence. Conclusions: A non-invasive algorithm based exclusively in a community setting is feasible to implement. Targeting risk factors, using a serial biomarker approach, we identified substantial number of cirrhosis which had not been detected previously. Disclosures:

Guruprasad P. Aithal - Advisory Committees or Review Panels: Aegerion Pharmaceuticals, Abbott, UK, LtD, Falk Pharma; Consulting: Biogen Idec, OTSUKA PHARMACEUTICAL EUROPE LTD, Basilea Pharmaceutica; Speaking and Teaching: Lilly

Indra Neil Guha - Grant/Research Support: Pfizer, Conatus

The following people have nothing to disclose: David J. Harman, Emilie A. Wilkes, Martin W. James, Stephen D. Ryder


The impact of Geography on organ allocation: Beyond the distance to the transplantation center

Rony Ghaoui/ Jone Garb

Baystate Medical Center, Springfield, MA

Purpose of the study: To measure the disparities in access to liver transplantation across UNOS region 1 using Geographic Information Systems (GIS) software. Methods: Based on OPTN data, the number of transplant registrations (candidates) and transplants by zip code in November 2012 was obtained. ZIP code listing rate was calculated as the number of candidates performed divided by the ZIP code population. Transplant listing rates by zip code were mapped using ArcGIS software. A choropleth (color-coded) map was generated to display the geographic distribution of 2012 listing rates. The Spatial Scan Statistic (SatScan software) was used to identify geographic areas (clusters) with rates significantly higher or lower than the rest of the region. Spatial regression analysis was performed to identify geographic and demographic factors in transplant listing rates. Factors tested included distance from the nearest transplant center, city over 50, 000 and population density. Results: A map of UNOS Region 1 transplant listing rates by zip code is shown in Figure 1 below. The map shows disparities in organ access to organ allocation across the region. Distance from the nearest transplant facility was the only significant factor in transplant listing rates identified by spatial regression. More importantly, SatScan cluster analysis identified areas with significantly high (red outlines) or low listing rates (purple outlines) that were not solely a function of distance to the transplant center. Conclusion: GIS represents a new approach to evaluat ing access to liver transplantation within a region, which can be used to guide efforts in alleviating disparities.



The following people have nothing to disclose: Rony Ghaoui, Jane Garb


Real World Costs of Telaprevir-based Triple Therapy, Including Costs of Managing Adverse Events, at the Mount Sinai Medical Center, NY: $195, 000 per SVR12

Kian Bichoupan, Valerie Martel-Laferriere, Michel Ng, Emily A. Schonfeld, Alexis Pappas, James F Crismale, Alicia Stivala, ViktoHya Khaitova, Donald Gardenier, Ponni Perumolswami, Thomas D.Schiano, Joseph A. Odin, Lawrence U. Liu, Douglas T. Dieterich, Andrea D. Branch

Division of Liver Diseases' Mount Sinai School of Medicine, New York, NY

Background and Aims: The addition of telaprevir to pegylatedinterferon and ribavirin has improved sustained virologic response (SVR) rates for genotype 1 HCV, but has also increased adverse events (AEs) and costs. We estimated the total management cost of triple therapy in a real-world setting. Methods: Pre-treatment, on-treatment, and post-treatment costs were calculated using 2010 US estimates from Medicare, Agency for Healthcare Research and Quality(AHRQ, ), and Red Book WAC, adjusting for inflation. Resource utilization was based on standard practices and data on 134 patients who initiated telaprevir use at Mount Sinai Medical Center (5/201112/2011). SVR12 was defined as an undetectable viral load weeks after the end of treatment. FIB-4 scores > 3. 25 indicated advanced fibrosis/cirrhosis. Results: Median age of the 134 patients was 57 years [interquartile range (IQR)=51-61], 91(68%) were male; 23 (17%) were black, 16 (12%) had HCV/HIV co-infection, 48 (36%) had advanced fibrosis/cirrhosis. Seventeen patients relapsed after the end of treatment; only 58 (43%) had an SVR12. Median cost of standard triple therapy (telaprevir, IFN/RBV and routine care) was $77, 020 ($66, 045-$92, 980) per patient. Median cost of standard triple therapy plus AE management was $84, 063 ($67, 967-$98, 1 38). 〇n an intention-to-treat basis, median total cost per SVR12 was $194, 216 ($156, 503 - $223, 162). Seventy-seven patients (57%) had AE-attributable costs; 49% received epoetin-a and 12% had a treatment-related hospitalization. For the 58 patients who completed 48 weeks of treatment, the median total cost was $98, 348 ($93, 412-$112, 772). Total cost was significantly lower for the 13 patients who completed response-guided therapy: $74, 890 ($74, 627-$85, 127), p<0.01. Median total cost for the 20 patients who discontinued due to AEs was $58, 933 ($28, 951$72, 579), and it was $67, 288 ($32, 600-$76, 371) for the 41 patients with on-treatment virologic failure. Based on these data, costs to treat 100 patients in the real world totaled to $7. 9 million, of which $3. 7 million (47% of the total) were spent on patients who failed to achieve an SVR. Conclusions: The median total cost of 48 weeks of telaprevir-based triple therapy was $98, 348, including costs of preparing the patient for treatment, AE management, and post-treatment SVR testing. The median total cost per SVR12 was $194, 216. Reductions in AEs are needed to optimize the clinical and economic effectiveness of HCV treatment (DK090317, DA0301095, CA152514).


Michel Ng - Speaking and Teaching: boehringer ingelheim, jaansen, gilead

Viktoriya Khaitova - Advisory Committees or Review Panels: Gilead, Vertex, Three River, Salix

Joseph A. Odin - Advisory Committees or Review Panels: Bristol Meyers Squibb

Douglas T. Dieterich - Advisory Committees or Review Panels: Gilead, Genentech, Janssen, achillion, idenix, Merck, Tobira, Boehringer Ingelheim, Tibotec, Inhibitex, Roche, Vertex

Andrea D. Branch - Grant/Research Support: Kadmon, Gilead, Janssen

The following people have nothing to disclose: Kian Bichoupan, Valerie MartelLaferriere, Emily A. Schonfeld, Alexis Pappas, James F. Crismale, Alicia Stivala, Donald Gardenier, Ponni Perumalswami, Thomas D. Schiano, Lawrence U. Liu


Cost-effectiveness of Hepatitis C Treatment by Primary Care Providers Supported by the Extension for Community Healthcare Outcomes (ECHO) Model

John B. Wong1, Karla A. Thornton2, Christie Carroll2, Sanjeev Aroro2

1Clinicol Decision Making, Tuffs Medicol Center, Boston, MA; 2Medicine, University of New Mexico, Albuquerque, NM

Purpose: The Extension for Community Healthcare Outcomes (ECHO) model has shown that hepatitis C(HCV) in underserved communities can be effectively treated by primary care providers, yielding a sustained viral response rate of 57. 5% in an underserved population with complex health problems. Cost concerns however may hinder ECHO dissemination, so we examined the cost-effectiveness of ECHO for HCV. Methods: Based on a prospective cohort study of ECHO-facilitated HCV treatment for 261 patients in 16 community sites and 5 prisons (NEJM 2011; 364: 2199), we updated and then used a previously published and validated cost-effectiveness model to compare ECHO to no antiviral therapy for each of the 261 patients. Costs included drugs, physician visits, lab tests, adverse events, HCV disease complications and multidisciplinary ECHO personnel (physician, pharmacist, psychiatrist, nurse manager, coordinator, user support analyst). We also performed an analysis of the cost of antiviral treatment if patients instead traveled to the academic center to receive care compared with ECHO personnel costs. Travel costs included mileage, patient time and for prisoners guard costs. We used quality of life adjustments to account for antiviral treatment and diseaserelated morbidity. Costs and effectiveness were discounted at 3% yearly. Results: ECHO access to HCV treatment increased discounted quality-adjusted life expectancy by 3. 8 (SD 1. 4) years overall, 3. 5 (SD 1. 3) years in the community and 4. 2 (SD 1. 4) years in the prison dwellers. ECHO dominated no antiviral therapy by resulting in lower lifetime costs and higher quality-adjusted life expectancies for 62% of the 261 patients and 55% of the community and 70% of the prison dwellers. Among the non-dominated patients, the incremental cost-effectiveness ratio of ECH〇 averaged $8300 (SD $7800) per qualityadjusted life year (QALY) gained overall, $9400 (SD $8500) in the community and $5900 (SD $5300) in prison dwellers, well below the standard US willingness to pay threshold of $50, 000 per QALY gained, making ECHO “cost-effective”. When comparing only antiviral treatment costs and travel and lost work time costs to ECHO costs (no disease costs), the mean savings from ECHO were $1352 per person or >$350, 000 for the 261 patients. For 10% of patients, travel costs were lower than ECHO costs because of their geographic proximity to the academic center. Conclusion: ECHO-facilitated HCV treatment is not only effective but also cost-effective, suggesting that ECHO provides resource efficient care access for underserved communities. Confirmation of these results in additional studies and in other diseases is needed and warranted.


The following people have nothing to disclose: John B. Wong, Karla A. Thornton, Christie Carroll, Sanjeev Arora


Impact of Treatment on Long-Term Morbidity and Mortality in Chronic Hepatitis C Patients Receiving Care Through the U. S. Veterans Health Administration

Jeffrey McCombs1, Tara Matsuda1,2, Ivy Tonnu-Mihara2, Sammy Saab3, Patricia Hines4, Gil L' Italian4, Timothy Juday4, Yong Yuan4

1Clinical Pharmacy and Pharmaceutical Economics and Policy, University of Southern California, Los Angeles, CA; -2Veterons Health Administration Hospital, Long Beach, CA; 3David Geffen School of Medicin, University of California-Los Angeles, Los Angeles, CA; 4Globol Health Economics and Outcomes Research, Bristol-Myers Squibb, Princeton, NJ

Objective: Document the impact of viral load suppression and treatment of risk of morbidity and mortality in patients with hepatitis C virus [HCV] infection receiving care through the U. S. Veterans Health Administration [VHA]. Methods: Study patients were selected from the VHA's HCV Clinical Case Registry [CCR] covering the period 1999-2012 if they had a detectable viral load [>25 IU/ml] and a recorded viral genotype. The primary outcomes were death and a composite of incident compensated cirrhosis, de-compensated cirrhosis, hepatocellular carcinoma (HCC) or a liver-related hospitalization, and were analyzed using Cox proportional hazards models. Time dependent variables were created for viral load and initiation of HCV-related treatment. Other potential risk factors include age, gender, race, ethnicity and viral genotype. Results: 128, 769 patients out of 360, 857 unique patients registered in the VHA HCV CCR database met all of the study inclusion criteria. The median length of follow-up was 6. 1 years [SE=3. 0]. Only 24. 3% of study patients initiated treatment and among treated patients, only16. 4% achieved an undetectable viral load at some point after starting treatment. Achieving undetectable viral load was associated with a reduced risk of composite events [adjusted HR=0.73; 95% CI=0.66-0.82] and death [adjusted HR=0.55; 95% CI=0.47-0.64]. Patients with genotype 2 are consistently at lower risk for death [adjusted HR=0.80; 95% CI=0.76-0.84] or the composite clinical endpoint [adjusted HR=0.77; 95% CI=0.74-0.80] relative to the more common genotype 1. Patients with genotype 3 are consistently at higher risk for the composite endpoint [adjusted HR=1. 11; 95% CI=1. 07-1. 16] and death [HR=1. 17; 95% Cl: 1. 11-1. 24] relative to patients with genotype 1. Age, male gender and white race were consistent predictors of increased risk for liver events and death. Conclusions: Treatment-induced viral load reduction, genotype and several demographic factors were found to be significantly associated with both long-term morbidity and mortality for CHC patients treated in the し. S. Veterans Health Administration. Our results use a large, real-world sample of HCV patients to verify earlier findings that viral load reduction through treatment can significantly reduce the risk of adverse patient outcomes in HCV patients.


Jeffrey McCombs - Consulting: BMS; Grant/Research Support: BMS Tara Matsuda - Grant/Research Support: BMS

Sammy Saab - Advisory Committees or Review Panels: BMS, Gilead, Merck, Vertex, Genentech; Grant/Research Support: Merck, Gilead; Speaking and Teaching: BMS, Gilead, Merck, Vertex, Genentech, Salix, Onyx, Bayer, Kadman; Stock Shareholder: Salix, Johnson and Johnson

Patricia Hines - Employment: Bristol-Myers Squibb

Timothy Juday - Employment: Bristol-Myers Squibb; Stock Shareholder: BristolMyers Squibb

Yong Yuan - Employment: Bristol Myers Squibb Company

The following people have nothing to disclose: Ivy Tonnu-Mihara, Gil L' Italian