Two decades of hepatitis E in solid organ transplantation: From endemic insight to unresolved therapeutic questions

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Nearly 2 decades after hepatitis E virus (HEV) was first recognized as a cause of chronic hepatitis in solid organ transplant (SOT) recipients by the Toulouse and Groningen teams,1,2 the field stands at an inflection point: while key principles of disease biology and treatment are now well established, critical aspects of clinical management remain surprisingly undefined. In this issue of Hepatology, Kamar et al.3 present a landmark monocentric experience spanning more than 20 years, offering one of the most comprehensive datasets on HEV infection in SOT recipients to date. In their cohort of 6452 transplant recipients in Toulouse, 228 patients (3.5%) were diagnosed with HEV infection. Chronic infection developed in nearly two-thirds of cases, confirming the well-established risk of persistence in immunocompromised hosts. Immunosuppressive regimen emerged as a key determinant: tacrolimus was independently associated with chronicity, whereas mycophenolic acid appeared protective. Ribavirin therapy guided by negative stool HEV RNA at the end of treatment achieved sustained virological response rates exceeding 90%, including in patients requiring retreatment after shorter ribavirin treatment. These findings consolidate much of what is known about HEV in transplantation. However, they also raise important questions, particularly regarding generalizability, immunity, and the persistent lack of standardization in prolonged or retreatment strategies (Figure 1).FIGURE 1: Main findings from Kamar et al.,3 open questions, and future research agenda. Generated using ChatGPT. Abbreviation: HEV, hepatitis E virus.A UNIQUE COHORT FROM A UNIQUE SETTING The Toulouse cohort represents both a major strength and a central challenge in interpreting these data. This region is widely recognized as a hotspot for HEV infection, with some of the highest reported seroprevalence rates in Europe. As such, the study provides a rare opportunity to observe HEV epidemiology and clinical outcomes in a setting of sustained viral exposure. Yet this context complicates interpretation. The relatively high number of identified HEV infections may reflect increased environmental exposure rather than intrinsic susceptibility of SOT recipients. At the same time, high background seroprevalence raises a counterintuitive possibility: could prior exposure confer partial protection against reinfection or severe disease? This duality, high exposure potentially driving both increased incidence and partial immunity, makes Toulouse a uniquely informative, yet potentially non-representative, setting. The current study offers a provocative but inconclusive signal in this regard. Only a single case of reinfection was identified across the cohort, inviting 2 competing interpretations. On the one hand, prior HEV exposure may provide partial protective immunity, even in immunosuppressed patients. On the other hand, the apparent rarity of reinfection may reflect limitations in follow-up. Indeed, surveillance was structured primarily during the first 12 months, with less systematic data collection thereafter. The rarity of reinfection may therefore reflect true partial immunity, but may equally be explained by limited long-term surveillance. Distinguishing between true immunological protection and observational bias remains an open question with important implications for screening and prevention strategies. WHAT THIS STUDY FIRMLY ESTABLISHES Despite these contextual complexities, the study delivers several robust and clinically relevant insights. First, it reinforces the central role of immunosuppression in shaping HEV outcomes. The association of tacrolimus with chronic infection and the protective signal of mycophenolic acid support immunosuppressive modulation as a key component of management. Notably, the protective effect of mycophenolic acid contrasts with its negative impact on vaccine responses, for example, against COVID-19,4 potentially explained by inhibition of HEV replication as observed in vitro.5 The analysis further suggests that reduction of immunosuppression can induce viral clearance in chronic, but not acute, HEV infection. Second, it confirms the effectiveness of ribavirin “off-label” therapy in real-world practice. The high sustained virological response rate, exceeding 90%, including with retreatment, underscores its position as the current standard-of-care. Third, the study validates prior observations on treatment monitoring. Earlier work demonstrated that persistent fecal HEV shedding during therapy predicts relapse and may guide treatment duration.6 These findings are now confirmed at a larger scale, supporting stool HEV RNA as a practical tool to individualize therapy and reduce relapse rates. Together, these findings represent a significant step toward more refined management of HEV infection. PROLONGED DEFINITIVE VERSUS MAINTENANCE THERAPY The results from this cohort demonstrate that negative stool HEV RNA at the end of ribavirin treatment is strongly associated with sustained virological response. This endpoint required a mean treatment duration of 5 months, with treatment extending up to 19 months in some patients. Prolonged therapy frequently required management of anemia with erythropoietin or transfusions. A relevant proportion of patients (5/37) did not achieve this endpoint, raising the question of optimal long-term management. Should ribavirin dosage be escalated with intensified anemia management to achieve viral clearance, or should treatment shift toward maintenance strategies aiming to suppress rather than eliminate HEV? While maintenance therapy may control viremia and prevent liver-related complications, it may also promote the emergence of ribavirin resistance. In this context, the impressive response rate of ribavirin should not obscure the variability and limitations of current management. Rather, it highlights the need to standardize prolonged and retreatment strategies and define evidence-based pathways for refractory disease. In addition, novel therapeutic options such as nucleoside analogues, neutralizing monoclonal antibodies, and adoptive HEV-specific T-cell therapies are urgently needed.7–9 SCREENING STRATEGY The study also reopens the discussion on optimal screening strategies. For much of the observation period, HEV testing was triggered by elevated liver enzymes, a pragmatic but inherently selective approach. Data from the later systematic screening phase suggest that HEV infection is rare in patients with normal liver enzymes. Indeed, in the first 12 months after transplantation, only 0.15% of patients were infected. However, the mean interval between transplantation and HEV infection with increased liver enzymes was 6 years; thus, it may be expected that 1%–2% of SOT patients are infected with HEV within a decade after transplantation, even in the absence of elevated liver enzymes. These data suggest that a targeted screening strategy may be sufficient to identify the majority of HEV infections in SOT patients, but it is far from comprehensive. Future studies should more precisely clarify the clinical impact of HEV infection in the absence of elevated liver enzymes and thus inform on the need for screening strategies that identify this subset of patients. THE ENIGMA OF INCREASED SUSCEPTIBILITY OF LIVER TRANSPLANT PATIENTS Surprisingly, HEV infection was more frequent in patients with liver transplants compared with patients with other organ transplants (5.5 vs. 3.1%), although out of all SOT patients, they usually follow a lower immunosuppression regimen. The authors suggest that enhanced liver tropism and/or different eating habits may contribute to this difference. In the absence of evidence for this hypothesis, we speculate that the difference in (observed) incidence is rather due to more careful monitoring of liver enzymes in liver transplant patients (what is denied by the authors), or due to a less efficient adaptive immune response due to

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.