Transplanting hepatitis C virus-positive livers into hepatitis C virus-negative patients with preemptive antiviral treatment: A modeling study

Abstract

Under current guidelines, hepatitis C virus (HCV)-positive livers are not transplanted into HCV-negative recipients because of adverse posttransplant outcomes associated with allograft HCV infection. However, HCV can now be cured post-LT (liver transplant) using direct-acting antivirals (DAAs) with >90% success; therefore, HCV-negative patients on the LT waiting list may benefit from accepting HCV-positive organs with preemptive treatment. Our objective was to evaluate whether and in which HCV-negative patients the potential benefit of accepting an HCV-positive (i.e., viremic) organ outweighed the risks associated with HCV allograft infection. We developed a Markov-based mathematical model that simulated a virtual trial of HCV-negative patients on the LT waiting list to compare long-term outcomes in patients: (1) willing to accept any (HCV-negative or HCV-positive) liver versus (2) those willing to accept only HCV-negative livers. Patients receiving HCV-positive livers were treated preemptively with 12 weeks of DAA therapy and had a higher risk of graft failure than those receiving HCV-negative livers. The model incorporated data from published studies and the United Network for Organ Sharing (UNOS). We found that accepting any liver regardless of HCV status versus accepting only HCV-negative livers resulted in an increase in life expectancy when Model for End-Stage Liver Disease (MELD) was ≥20, and the benefit was highest at MELD 28 (0.172 additional life-years). The magnitude of clinical benefit was greater in UNOS regions with higher HCV-positive donor organ rates, that is, Regions 1, 2, 3, 10, and 11. Sensitivity analysis demonstrated that model outcomes were robust.

Conclusion: Transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy could improve patient survival on the LT waiting list. Our analysis can help inform clinical trials and minimize patient harm. (Hepatology 2018;67:2085-2095).

Figure 1. Model schematic showing the pathway of patients accepting HCV-positive or HCV-negative livers

For each patient profile, the model simulated two scenarios: (1) accept any liver, and (2) accept only HCV-negative livers. Patient open to accepting any liver had a higher likelihood of receiving a LT. Patients receiving an HCV-positive liver were treated preemptively with DAAs. These patients had a higher risk of graft failure and could remain viremic (if treatment was not successful) after LT. Abbreviations: LT, Liver transplant; DAA, Direct-acting antivirals; HCV, hepatitis C virus; QALYs, quality-adjusted life years; SVR, sustained virologic response; OPTN, Organ Procurement Transplant Network.

Figure 2. Change in life years if HCV-negative patients on the transplant waiting list are willing to accept any liver versus accept only HCV-negative livers

The clinical benefits are dependent on the MELD scores at which patients are willing to accept an HCV-positive liver. Starting at a MELD ≥ 20, patients benefit from accepting any liver. The highest clinical benefit of accepting any liver is seen at MELD 28. Abbreviations: MELD, model for end-stage liver disease; HCV, hepatitis C virus.

Figure 3. Change in life years by UNOS region if HCV-negative patients on the transplant waiting list are willing to accept any liver versus accept only HCV-negative livers

Patients benefit from becoming open to accepting an HCV-positive liver at MELD 20 and beyond, irrespective of the UNOS region, although the magnitude of benefit varied by region. Abbreviations: UNOS, United Network for Organ Sharing, MELD, model for end-stage liver disease; HCV, hepatitis C virus

Figure 4. Regional results showing the correlation between HCV-positive organ rate and the health benefits within a UNOS region

The magnitude of clinical benefit was proportional to the HCV-positive organ rates of the region—larger in regions having higher HCV-positive organ rates including Regions 1, 2, 3, 10 and 11. Abbreviations: HCV, Hepatitis C Virus; MELD, Model for end-stage disease; UNOS, United Network for Organ Sharing; R1–11, UNOS Regions 1–11

Figure 5

Tornado diagram showing the 10 most sensitive model parameters in MELD 20, i.e. the cutoff score to accept HCV-positive liver, and in MELD 28, i.e. the MELD score with the highest gain in life years. In both cases, HCV-positive organ rate had the highest impact on the primary model outcome, i.e. change in life years. *Parameters having a value by each MELD score. Basically, we used +/− 25% change from baseline values **Post-LT corresponds to Post-LT (Non-viremic) and Post-LT (SVR) stages in the model. ***Post-LT Viremic correspond to stages including salvage therapy, F0–F2, and F3–F4 in HCV-positive arm in the model Abbreviations: HCV, hepatitis C virus; LT, liver transplant; SVR, sustained virologic response; GR, graft failure; TP, transition probability