1. 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

2. 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

3. 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

4. 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”

5. Dilemma: Optimal Timing of HCV Treatment

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

7. 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)

8. 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

9. 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

10. 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:

11. 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

12. Model Results

13. Model Validation: Patient Survival

14. Life Expectancy: Pre-LT vs Post-LT

15. 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

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

17. 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…

18. 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

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

20. 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

21. 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

22. 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