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Early Transplantation for Alcohol-associated Hepatitis Improves Survival

Key findings

  • In a mathematical model of highly selected hypothetical patients with severe alcohol-associated hepatitis having characteristics similar to patients in ACCELERATE-AH trial, offering early liver transplantation increased life expectancy fourfold compared with requiring six months of sobriety before eligibility
  • Sustained alcohol use after transplantation did not eliminate this benefit but resulted in a 67% loss of the life expectancy gained by early transplantation followed by complete abstinence
  • Even in the most extreme scenario—in which all early transplant recipients returned to sustained alcohol use and all delayed recipients maintained complete abstinence afterward—survival with early transplantation was twofold better

Early liver transplantation for highly selected patients with alcohol-associated hepatitis (AH) is a relatively new indication, but the change has not come without controversy. Intermediate survival rates after early transplantation for AH are acceptable (about 85% at three years), but some recipients may resume using alcohol afterward and are at risk for poorer outcomes. Therefore, many centers still require a minimum period of alcohol abstinence, usually six months, before listing a patient with AH for transplantation.

Using a mathematical model, Brian P. Lee, MD, MPH, of the University of California, San Francisco (UCSF), Sumeyye Samur, PhD, former postdoctoral fellow at Massachusetts General Hospital's Institute for Technology Advancement (ITA), Jagpreet Chhatwal, PhD, senior scientist at the ITA, and Norah A. Terrault, MD, MPH, UCSF, and colleagues determined that early liver transplantation for highly selected patients with AH increased life expectancy by about fourfold compared with requiring six months of sobriety. In Gastroenterology, they report this was true regardless of the estimated risk of sustained alcohol use after transplantation.

The Model

The researchers adapted a previously validated Markov-based mathematical model, published in Hepatology, to simulate a virtual trial of 10,000 hypothetical patients with AH as the first presentation of liver disease. They simulated the long-term outcomes of early versus delayed transplantation.

Data for the model were drawn from the United Network of Organ Sharing (UNOS) database, the American Consortium of Early Liver Transplantation for Alcoholic Hepatitis (ACCELERATE-AH) trial and other published studies.

All patients who received a liver transplant were categorized into one of three alcohol use categories after transplantation: abstinent, slip (alcohol use followed by sobriety) and sustained use. The likelihood of using alcohol was informed by ACCELERATE-AH data. Patients could also experience graft failure after transplantation, with the likelihood dependent on their alcohol use category.

Outcomes

The primary outcome was life expectancy, measured in life-years from the date of hospitalization for AH.

Outcomes by rate of alcohol use were as follows:

  • Base case analysis (the risk of sustained alcohol use and slips was assumed to be equivalent for all patients): Life expectancy was about 4x higher with early transplantation (6.55 years vs. 1.46 years with delayed transplantation)
  • Extreme analysis #1 (no patient had any alcohol use while awaiting delayed transplantation but maintained the same risk of post-transplantation alcohol use as in the base case analysis): Life expectancy was 6.55 years with early transplantation and 1.81 years with delayed transplantation
  • Extreme analysis #2: Life expectancy was 10.85 years for patients who underwent early transplantation with no alcohol use afterward, but 3.62 years in a scenario where all transplant recipients had sustained alcohol use after transplantation. Thus, sustained alcohol use after early transplantation was associated with 7.23 years lost, or about 67% of the life expectancy gained from early transplantation
  • Most extreme analysis (all patients had sustained alcohol use after early transplantation and no patient had any alcohol use after delayed transplantation): Life expectancy remained better with early transplantation (3.62 years vs. 2.30 years with delayed transplantation)

As a middle ground, some centers are specifying a period of sobriety that's shorter than six months. The researchers modified the base case analysis accordingly. Outcomes by duration of abstinence were as follows:

  • When the period of mandatory sobriety was three months, life expectancy with delayed transplantation increased from 1.46 years in the base case analysis to 2.32 years
  • When the period was one month, life expectancy was 3.92 years
  • Note that in both scenarios, life expectancy remained substantially lower than the 6.55 years observed with early transplantation in the base case analysis

Outcomes by Lille and MELD Scores

Early transplantation provided a net increase in life expectancy across all Model for End-Stage Liver Disease (MELD) and Lille scores. The net increase in life expectancy with early transplantation was highest in patients with Lille score of 0.5–0.82 on day 7 of hospitalization and MELD score ≥32.

Takeaways for Clinicians

These findings support the use of liver transplantation with no minimum period of sobriety before surgery as definitive therapy for patients with severe AH.

There appears to be value in considering Lille score when making policies about early transplantation for AH.

Policies requiring three months of alcohol abstinence before transplantation are not as beneficial as early liver transplantation for patients with AH.

Patients should be counseled that returning to sustained alcohol use after early transplantation may substantially decrease their life expectancy.

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