Cytomegalovirus Reactivation Is Associated With Lower Rates of Hepatocellular Carcinoma Recurrence After Liver Transplantation

Abstract

Cytomegalovirus; Hepatocellular carcinoma; Liver transplantation

Citomegalovirus; Carcinoma hepatocel·lular; Trasplantament de fetge

Citomegalovirus; Carcinoma hepatocelular; Trasplante de hígado

In patients with hepatocellular carcinoma (HCC), undergoing liver transplantation (LT), cytomegalovirus reactivation (CMVr) may modulate the immune system to prevent tumor recurrence. In this multicenter retrospective study (2010–2015) involving 15 institutions, we assessed the effect of early CMVr in tumor recurrence rates among 771-LT HCC patients with tacrolimus-based immunosuppression (88% men, mean age 58 years). CMV prophylaxis was implemented for 19.7% of patients, while the rest were managed with preemptive therapy. The Milan criteria were met by 88% of patients. Microvascular invasion was present in 12.7% of explanted livers. The serum AFP level before transplantation was 5.1 (3–15) ng/mL. After a median follow-up of 7.4 years, 101 patients (13%) experienced HCC recurrence. CMVr occurred in 235 patients (30.5%) at a median of 41.5 days post-LT and 42 patients (5.6%) had CMV disease. Cumulative exposure to tacrolimus within the first 3 months after LT was similar among patients with and without CMVr. In a multivariate Cox regression analysis, factors associated with an increased rate of HCC recurrence included microvascular invasion [HR:2.82, CI95%:1.55–5.14; p 0.0001], donation after circulatory determination of death [HR:4.43,CI95%:1.52–12.9; p 0.006) and diameter of the main nodule at explant [HR:1.04, CI95%:1.02–1.06; p < 0.001]. Meanwhile CMVr [HR:0.46, CI95%:0.23–0.93, p 0.031] and MELD [HR:0.93, CI95%:0.87–0.99; p0.017] exhibited protective effects. In conclusion, early CMVr may protect against HCC recurrence. The underlying immune mechanisms warrant further investigation.

The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by competitive grants from the Instituto de Salud Carlos III (grant numbers: PI13/01770 and PI18/01759), and co-financed by the European Regional Development Fund “A way to achieve Europe.” AC-G and MB were also supported by the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) (https://www.ciberehd.org/), which is funded by the Instituto de Salud Carlos III (co-financed by the European Regional Development Fund). VA has received a grant from the AEEH (Asociación Española para el Estudio del Hígado, Spain): Beca de Intensificación. AC-G received a postdoctoral Fellowship from CiberEHD and MB was supported by competitive grants from the Instituto de Salud Carlos III (grant numbers PI23/00088 and INT24/00021) and by Generalitat Valenciana (grant numbers AICO/2021/035 and CIPROM/2023/16). Victoria Aguilera received a grant from the AEEH “Beca de intensificación para investigadores” in 2021. LM-A was supported by the Instituto de Salud Carlos III (grant numbers FI20/00033 and MV22/00053).