Optimal Timing of Hepatitis C Treatment for Patients on the Liver Transplant Waiting List Jagpreet Chhatwal, PhD,1,2 Sumeyye Samur, PhD1,2 Brian Kues, MS,3 Turgay Ayer, PhD,3 Mark S. Roberts, MD, MPP,3 Fasiha Kanwal, MD, MSHS,5,6 Chin Hur, MD,1,2 Drew MS Donnell,3,4 Raymond T. Chung, MD1,2   1Massachusetts General Hospital, Boston, MA, 2Harvard Medical School, Boston, MA 3Department of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA USA, 3Department of Health Policy and Management, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA, 4Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA, 5Department of Medicine, Baylor College of Medicine, Houston, TX USA, 6Houston Veterans Affairs Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center

Jagpreet Chhatwal I disclose the following financial relationship(s) with a commercial interest: Consulting: Complete HEOR Solutions; Gilead; Merck & Co., Inc. Grant/Research Support: NIH/National Center for Advancing Translational Sciences Intro, welcome questions and comments during presentation, and ask how many people had used LL previously. © 2016 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG

Benefits of Oral DAAs for Liver Transplant Candidates The availability of oral DAAs has altered the treatment paradigm for both pre- and post-LT patients Treatment is now feasible with high success rates Improvements in MELD score Reduced rate of HCV recurrence post LT and need for re-transplantation SVR  fibrosis stabilization or regression and improved graft survival

Treat HCV pre- or post-LT? Pros of Pre-LT Treatment Cons of Pre-LT Treatment Pre-LT treatment of HCV can improve patients’ MELD score and improve survival on the wait list Waiting until the LT could result in worsening of the underlying liver condition and increase the likelihood of mortality on the waiting list Pre-LT treatment could delay patients’ liver transplant by moving them further down the waiting list By improving MELD score by a few points, some patients could also fall below the range for liver transplantation without obviating the need for liver transplant “MELD limbo” or “MELD purgatory”

Dilemma: Optimal Timing of HCV Treatment

Objective To identify LT-eligible patients with decompensated cirrhosis who will benefit (and not benefit) from pre-LT treatment based on their MELD scores

Approach Ideally, a randomized controlled trial could inform the optimal timing of HCV treatment However, such a trial will be prohibitively large and time consuming In such situations, mathematical modeling can inform optimal strategies We simulated a virtual trial comparing long-term outcomes of pre- versus post-LT HCV treatment with oral DAAs for patients having MELD scores between 10 and 40 We developed a Markov-based microsimulation model that simulated the life course of patients SIM-LT (Simulation of Liver Transplant Candidates)

SIM-LT (Simulation of Liver Transplant Candidates) Pre-LT Disease progression Post-LT Disease Progression Patient demographics Efficacy of HCV Treatment Outcomes SIM-LT Model HCV Treatment Pre- vs Post-LT Life years for each MELD score QALYs for each MELD score Outcomes by UNOS region 1-year and 5-year transplant survival (validation) Changes in MELD Scores Quality of Life Changes in Transplant Waiting List Likelihood of Liver Transplant So that we can generate clinical outcomes including LY, survival, QALYs

Simulation of Timing of HCV Treatment SVR INPUTS Antiviral Treatment Patient characteristics Mortality rates Transition probabilities Quality of life Treatment efficacy Post-LT Treatment OUTPUTS HCV- Waiting List Life years QALYs 1-year & 5-year patient survival No SVR Liver Transplant   HCV+ F0–F2 F3–F4 Pre-LT Treatment Waiting List Validated with OPTN data   Graft Failure Model to be clinically as clinically realistic as possible. Our model included “cinical realities”… We considered the availability of HCV+ donors All-cause Death Liver-related Death

Model Inputs Patient characteristics Treatment efficacy Decompensated cirrhosis having MELD scores in the range of 10–40 mean age: 50 HCV genotypes 1 or 4 Treatment efficacy SOLAR 1 and SOLAR 2 (sofosbuvir and ledipasvir) Likelihood of liver transplant Massie et al. 2011 Considered reduced likelihood of LT due to loss of access to HCV+ donor organs Considered reduced likelihood of LT due to loss of access to HCV+ donor organs Massie AB, et al. MELD Exceptions and Rates of Waiting List Outcomes. Am J Transplant 2011;11:2362-2371.

Inputs: MELD Score Change MELD score change on the LT waiting list UNOS data MELD score change after achieving SVR SOLAR 1 and SOLAR 2 New paper? Gane et al., AASLD 2015 Abstract 1049

Model Results

Model Validation: Patient Survival

Life Expectancy: Pre-LT vs Post-LT

HCV Treatment Pre- OR Post-LT? Pre-LT Treatment Improves Life Expectancy Difference in life years if HCV is treated pre-LT versus post-LT

HCV Treatment Pre- OR Post-LT? Pre-LT Treatment Improves QALYs Difference in QALYs if HCV is treated pre-LT versus post-LT

Variations in Results by UNOS Regions: UNOS Region 3 Pre-LT Treatment Improves Life Expectancy We then explored the impact of variable wait times across UNOS regions on outcomes—wait time vary substantially across regions We first selected the shortest wait time region—REGION 3. ADD text pop up…

HCV Treatment Pre- OR Post-LT? UNOS Region 9 Pre-LT Treatment Improves Life Expectancy In contrast, we analysed the longest wait time region.. Improvement in LY was greater at lower MELD scores

Comparison by UNOS Region Makes a huge difference esp in regions with long waiting times Longer the wait time, the higher the threshold

Limitations While the guidance offered by this model is useful, recommendations may still need to be individualized for special situations For example, our results may not apply where patients’ urgency for LT is not determined by MELD score Our analysis did not consider patients with HCC We did not explicitly model Child Turcotte-Pugh class in our analysis We did not model patient dropout from the waiting list resulting from MELD improvement Extrahepatic complications not captured by MELD scores

Conclusions We conducted a comprehensive analysis of the tradeoffs of HCV treatment pre- versus post- liver transplant Optimal MELD score threshold below which to treat HCV in patients on the transplant waiting list is between MELD scores 23–27, depending on the UNOS region Our results may help inform clinicians about the timing of HCV treatment in liver transplant candidates

Optimal Timing of Hepatitis C Treatment for Patients on the Liver Transplant Waiting List Jagpreet Chhatwal, PhD,1,2 Sumeyye Samur, PhD1,2 Brian Kues, MS,3 Turgay Ayer, PhD,3 Mark S. Roberts, MD, MPP,3 Fasiha Kanwal, MD, MSHS,5,6 Chin Hur, MD,1,2 Drew MS Donnell,3,4 Raymond T. Chung, MD1,2   1Massachusetts General Hospital, Boston, MA, 2Harvard Medical School, Boston, MA 3Department of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA USA, 3Department of Health Policy and Management, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA, 4Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA, 5Department of Medicine, Baylor College of Medicine, Houston, TX USA, 6Houston Veterans Affairs Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center