Why Hepatitis E Remains a Silent Threat in Transplant Recipients: Key Insights from Two Decades of Data

Highlights

• Hepatitis E virus (HEV) infection was diagnosed in 3.53% of solid organ transplant (SOT) patients over two decades, with significantly higher rates among liver transplant recipients.
• Two-thirds of infected patients developed chronic hepatitis, with tacrolimus use identified as an independent risk factor for chronicity, while mycophenolic acid demonstrated protective effects.
• Extended ribavirin therapy achieving complete serum and stool HEV RNA clearance achieved a 91.5% sustained virological response rate, though three patients succumbed to decompensated HEV-related cirrhosis.
• Extrahepatic manifestations, including neurological symptoms and glomerular diseases, occurred in a minority of patients and often resolved with viral clearance.

Background: The Underrecognized Challenge of Hepatitis E in Transplantation

Hepatitis E virus infection has historically been considered a self-limiting acute illness in immunocompetent individuals, primarily transmitted through contaminated water in endemic regions. However, over the past two decades, recognition of HEV as a significant pathogen in immunocompromised populations has grown substantially. Among solid organ transplant recipients, HEV infection presents unique challenges due to the interplay between viral persistence and lifelong immunosuppression required to prevent graft rejection.

The clinical significance of HEV in SOT patients extends beyond acute hepatitis. Reports of chronicity, rapid progression to cirrhosis, and associated extrahepatic complications have prompted increased awareness and systematic screening protocols in transplant centers worldwide. Despite this growing recognition, comprehensive data on long-term outcomes, optimal treatment strategies, and predictors of chronicity remain limited.

This gap in knowledge has substantial clinical implications. Transplant clinicians require evidence-based guidance on screening frequency, risk stratification, and therapeutic decision-making. The study by Kamar and colleagues addresses these critical questions through an analysis of two decades of experience in a large cohort of SOT patients.

Study Design: A Comprehensive Two-Decade Retrospective Analysis

The investigation conducted by researchers represents a retrospective, single-center study analyzing 6,452 solid organ transplant patients followed between 2001 and 2024 at a major transplantation center. The study population encompassed recipients of various organ transplants, providing a comprehensive overview of HEV epidemiology across the transplant spectrum.

Screening protocols evolved during the study period. Prior to 2016, HEV testing was performed systematically in cases of elevated liver enzymes, reflecting a reactive rather than proactive approach. Recognizing the limitations of symptom-driven testing, the institution implemented universal HEV screening at 3- and 12-months post-transplantation beginning in 2016. This prospective screening strategy enabled identification of asymptomatic infections and provided more accurate incidence data.

The study assessed multiple endpoints including incidence rates, natural history of infection, treatment responses, and extrahepatic manifestations. Chronic hepatitis was defined as persistent HEV viremia beyond three months following documentation of acute infection, consistent with established definitions in the field.

Key Findings: High Chronicity Rates and Treatment Outcomes

Incidence and Risk Stratification

Among the 6,452 SOT patients followed over the 23-year period, HEV infection was diagnosed in 228 patients, yielding an overall incidence of 3.53%. This figure underscores the substantial burden of HEV in transplant populations, considerably higher than rates observed in the general immunocompetent population. Notably, incidence was significantly higher among liver-transplant patients compared to recipients of other solid organs, suggesting that the transplanted liver itself may serve as both a target and potential source of HEV infection.

Natural History: Chronicity vs. Spontaneous Clearance

At three months post-HEV documentation, the natural history outcomes revealed a concerning pattern. Approximately 65.1% of infected patients developed chronic hepatitis, reflecting the profound impact of immunosuppression on viral persistence. Conversely, 34.9% of patients achieved spontaneous viral clearance, demonstrating that some transplant recipients can mount effective immune responses against HEV despite ongoing immunosuppression.

Analysis of immunosuppressive regimens identified critical predictors of chronicity. Tacrolimus use emerged as independently associated with chronic HEV infection, highlighting the role of calcineurin inhibitors in impairing viral clearance. In contrast, mycophenolic acid demonstrated protective effects, reducing the likelihood of chronicity. This finding has important implications for immunosuppressive management in HEV-infected transplant patients and suggests potential therapeutic strategies targeting immunosuppression modification.

Treatment Responses and Sustained Virological Outcomes

Ribavirin remained the cornerstone of antiviral therapy throughout the study period. The overall sustained virological response (SVR) rate of 91.5% reflects excellent treatment efficacy when therapy was appropriately extended until complete serum and stool HEV RNA clearance. This underscores the importance of comprehensive viral monitoring, including both blood and stool specimens, to confirm true viral eradication before treatment cessation.

Despite the generally favorable treatment outcomes, a minority of patients required multiple treatment courses or experienced treatment failure. These challenging cases highlight the need for alternative therapeutic approaches and closer monitoring strategies. Most concerning, some patients developed cirrhosis or died while viremic, including three patients who succumbed to decompensated HEV-related cirrhosis. These outcomes emphasize the potentially devastating natural history of chronic HEV in transplant recipients when viral clearance cannot be achieved.

Extrahepatic Manifestations

Beyond hepatic complications, HEV infection in this cohort was associated with significant extrahepatic manifestations. Neurological symptoms were documented in 2.2% of patients, consistent with emerging evidence linking HEV to neuroinvasive disease. Glomerular diseases occurred in 3.9% of the cohort, manifestations that often resolved with achievement of viral clearance, suggesting a direct pathophysiological role of HEV in these renal complications. These findings expand the clinical spectrum of HEV-associated disease and reinforce the importance of considering HEV in transplant patients presenting with unexplained neurological or renal symptoms.

Expert Commentary: Interpreting the Clinical Implications

The findings from this extensive retrospective analysis carry significant weight for transplant clinical practice. The 3.5% incidence rate, while seemingly modest, translates to substantial absolute numbers given the growing transplant population worldwide. The predominance of chronicity, with nearly two-thirds of patients developing persistent infection, underscores the vulnerability of immunosuppressed individuals to viral persistence.

The identification of tacrolimus as a chronicity risk factor and mycophenolic acid as protective offers clinicians actionable insights. Immunosuppression modification, particularly reduction of tacrolimus exposure when feasible, may facilitate spontaneous clearance or improve treatment responses. This approach must be balanced against the risk of graft rejection, exemplifying the complex risk-benefit calculations inherent in transplant medicine.

The 91.5% SVR rate with ribavirin therapy is encouraging, but the requirement for extended treatment until complete viral clearance in both serum and stool represents a more demanding endpoint than previously applied in many centers. The correlation between treatment duration and SVR emphasizes the need for rigorous monitoring protocols and patient adherence support.

Several limitations warrant consideration. The single-center, retrospective design introduces potential selection biases and limits generalizability to other populations with different HEV genotypes or healthcare contexts. The evolution of screening practices over the study period may have affected incidence estimates. Additionally, the impact of newer immunosuppressive agents not extensively used during the study period remains to be evaluated.

Conclusion: Mandatory Screening and Individualized Management

This two-decade analysis establishes hepatitis E as a frequent and clinically significant complication in solid organ transplantation. With over 3.5% of patients affected and chronicity rates exceeding 65% in those infected, HEV poses substantial risks for long-term graft and patient outcomes. The identification of modifiable risk factors—particularly immunosuppressive agents—provides opportunities for therapeutic optimization.

Extended ribavirin therapy remains highly effective, but success depends on achieving complete viral clearance from both serum and stool. The documented extrahepatic manifestations underscore that HEV is not merely a hepatotropic virus but can affect multiple organ systems, necessitating vigilance for diverse clinical presentations.

The authors’ conclusion that screening for HEV is mandatory in SOT patients with elevated liver enzymes reflects a consensus increasingly adopted by transplant societies worldwide. Implementation of routine screening protocols, particularly at strategic timepoints post-transplantation, may enable earlier detection and intervention before chronic infection and its complications become established.

Future directions include evaluation of novel antiviral agents, optimized immunosuppression strategies for HEV-infected patients, and expanded understanding of HEV genotype-specific outcomes. Until such data emerge, the findings from this landmark study provide robust evidence supporting proactive screening and aggressive pursuit of viral clearance in affected transplant recipients.

References

1. Kamar N, Abravanel F, Marion O, et al. Two decades of hepatitis E in solid organ transplantation: A retrospective monocentric analysis. Hepatology. 2026 Apr 3. PMID: 41931106.
2. Kamar N, Garrouste C, Haagsma EB, et al. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011;140(5):1481-1489.
3. Haagsma EB, van den Berg AP, Porte RJ, et al. Chronic hepatitis E virus infection in liver transplant recipients. Liver Transpl. 2008;14(4):547-553.
4. Kamar N, Izopet J, Tripon S, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. N Engl J Med. 2014;370(25):2447-2448.
5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018;68(6):1256-1271.