CMV Refractory and Resistant Infection in Solid Organ Transplant Recipients in Argentina

Evaluation of Cytomegalovirus Refractoriness and Resistance in Solid Organ Transplantation in Argentina: A Multicenter Study

This study will describe the frequency and characteristics of refractory and resistant cytomegalovirus (CMV) infection in adults who received a solid organ transplant in Argentina between 2017 and 2024. Researchers will review medical records from transplant centers across the country to identify episodes of CMV infection that did not respond adequately to standard antiviral treatment (refractory) or that showed genetic mutations associated with drug resistance. The study will describe the clinical features, treatments used, and outcomes (including graft function and survival) of patients with these episodes, in order to better understand how common this problem is and what factors are associated with it in the local population.

Study Overview

• Status: Not yet recruiting
• Conditions: Cytomegalovirus Infections; Solid Organ Transplantation; Solid Organ Transplantation Recipient

Detailed Description

Cytomegalovirus (CMV) remains one of the most frequent infections after solid organ transplantation (SOT), with important direct and indirect effects on graft and patient survival. While preventive strategies (prophylaxis and preemptive therapy) have reduced CMV-related disease and mortality, refractory and resistant CMV infection continues to be a major challenge, particularly in high-risk transplants (donor-positive/recipient-negative serostatus, and those receiving thymoglobulin induction). No epidemiological data on refractory or resistant CMV currently exist in Argentina.

This multicenter retrospective cohort study will include adult (≥18 years) solid organ transplant recipients from participating centers in Argentina who developed CMV infection within 18 months post-transplant, between January 1, 2017 and December 31, 2024. Cases meeting pre-specified operational criteria for refractory or resistant CMV infection will be identified from medical records. Refractory infection is defined as viral load that does not decrease or increases after two weeks of appropriate antiviral treatment; resistant infection is defined as refractory infection with documentation of at least one genetic mutation (UL97 and/or UL54) associated with antiviral resistance, confirmed through genotyping performed at the national reference laboratory (Instituto Malbrán).

Data will include demographic and transplant-related variables, immunosuppression regimen, virological monitoring, antiviral treatment lines and dosing, resistance genotyping results when available, and clinical outcomes including graft function, rejection episodes, and mortality at 90 days and one year. Data will be collected, coded, and stored in a centralized, de-identified database (REDCap) for descriptive and comparative statistical analysis.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Emilio Felipe Huaier Arriazu, MD; Phone Number: 8165 / 9542 +549 011 49590200; Email: emilio.huaier@hospitalitaliano.org.ar
• Study Contact Backup: Name: Laura Alicia Barcan, MD; Phone Number: 8206 +549 1149590200; Email: laura.barcan@hospitalitaliano.org.ar

Study Locations

• Argentina
  • Buenos Aires F.D.
    • Buenos Aires, Buenos Aires F.D., Argentina, 1199
      • Hospital Italiano de Buenos Aires
      • Sub-Investigator: Emilio Felipe Huaier Arriazu, MD
      • Contact: EMILIO Felipe HUAIER ARRIAZU, MD; Phone Number: 8165 / 9542 +54911-49590200; Email: emilio.huaier@hospitalitaliano.org.ar
      • Contact: Laura Alicia Barcan, MD; Phone Number: 8206 +54911-49590200; Email: laura.barcan@hospitalitaliano.org.ar
      • Sub-Investigator: Astrid Smud, MD
      • Principal Investigator: Laura Alicia Barcan, MD
      • Sub-Investigator: Natalia Pujato, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients (≥18 years) who received a solid organ transplant (kidney, liver, heart, lung, pancreas, or combined transplant) at one of the participating centers in Argentina, and who developed cytomegalovirus (CMV) infection within 18 months following transplantation, during the period from January 1, 2017 to December 31, 2024. Cases are identified retrospectively from the transplant databases and medical records of each participating center.

Description

Inclusion Criteria:

• Adult patients (≥18 years) who received a solid organ transplant (kidney, liver, heart, lung, pancreas, or combined) at a participating center in Argentina between January 1, 2017 and December 31, 2024
• Documented CMV infection within 18 months post-transplant
• Followed for at least 18 months from transplant and at least 12 months from CMV infection onset

Exclusion Criteria:

• Patients with incomplete medical records precluding assessment of CMV infection status or key study variables
• Patients not meeting the minimum follow-up period from transplant or from infection onset

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
CMV-infected SOT recipients; Adult solid organ transplant recipients (kidney, liver, heart, lung, pancreas, or combined transplants) who developed CMV infection within 18 months post-transplant between 2017 and 2024, followed to identify episodes meeting criteria for refractory or resistant infection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of refractory or resistant CMV infection	Proportion of solid organ transplant recipients with CMV infection who meet operational criteria for refractory infection (viral load unchanged or increased after 2 weeks of appropriate antiviral treatment) or resistant infection (refractory infection plus documented genetic mutation, e.g. UL97 and/or UL54, associated with antiviral resistance)	Within 18 months post-transplant, assessed retrospectively for the period January 2017 to December 2024

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of overall CMV infection	Proportion of SOT recipients with any CMV infection (primary infection, reactivation, asymptomatic infection, or disease), stratified by transplanted organ	Within 18 months post-transplant, 2017-2024
Distribution of clinical forms of CMV infection	Classification of CMV episodes as primary infection, reactivation, asymptomatic infection, or CMV disease	Within 18 months post-transplant, 2017-2024
Frequency of antiviral resistance mutations	Proportion of genotyped refractory CMV episodes with ≥1 resistance-associated mutation (UL97 and/or UL54)	From T3 (declaration of refractoriness) to T4 (episode resolution), up to 12 months
Antiviral treatment lines and combination therapy use	Number of antiviral treatment lines used per episode (1, 2, ≥3) and proportion of episodes receiving combination antiviral therapy (≥2 active agents ≥72h)	From T2 (treatment initiation) to T4 (negativization) or last available PCR if not resolved, up to 12 months
All-cause mortality	Proportion of patients who died at 90 days and at 1 year after the CMV refractory/resistant episode	90 days and 1 year post-episode onset
Graft outcome	Proportion of patients with graft loss or rejection following the CMV refractory/resistant episode	rejection following the CMV refractory/resistant episode Through 1 year post-episode onset
Association between mutation type and antiviral treatment received	Distribution of antiviral treatment regimens received (ganciclovir, foscarnet, letermovir, maribavir, cidofovir, combination therapy) according to mutation type detected (UL97 vs. UL54 vs. none)	From T2 (antiviral treatment initiation) to T4 (episode resolution), up to 12 months
Virologic response	Time to virologic negativization (two consecutive negative PCR results ≥7 days apart)	From T2 (treatment initiation) to T4 (confirmed negativization), up to 12 months, with censoring at last available PCR for patients not achieving negativization

Collaborators and Investigators

• Sponsor: Hospital Italiano de Buenos Aires
• Collaborators: Takeda Pharmaceuticals North America, Inc.

Publications and helpful links

General Publications

• Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019 Apr 8;68(8):1420-1426. doi: 10.1093/cid/ciy696.
• Kotton CN, Kumar D, Manuel O, Chou S, Hayden RT, Danziger-Isakov L, Asberg A, Tedesco-Silva H, Humar A; Transplantation Society International CMV Consensus Group. The Fourth International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. Transplantation. 2025 Jul 1;109(7):1066-1110. doi: 10.1097/TP.0000000000005374. Epub 2025 Apr 9. No abstract available.
• Navarro D, Fernandez-Ruiz M, Aguado JM, Sandonis V, Perez-Romero P. Going beyond serology for stratifying the risk of CMV infection in transplant recipients. Rev Med Virol. 2019 Jan;29(1):e2017. doi: 10.1002/rmv.2017. Epub 2018 Oct 25.
• Mehta Steinke SA, Alfares M, Valsamakis A, Shoham S, Arav-Boger R, Lees L, Ostrander D, Forman MS, Shedeck A, Ambinder RF, Jones RJ, Avery RK. Outcomes of transplant recipients treated with cidofovir for resistant or refractory cytomegalovirus infection. Transpl Infect Dis. 2021 Jun;23(3):e13521. doi: 10.1111/tid.13521. Epub 2020 Dec 2.
• Tamzali Y, Pourcher V, Azoyan L, Ouali N, Barrou B, Conti F, Coutance G, Gay F, Tourret J, Boutolleau D. Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection. Transpl Int. 2023 Jun 15;36:11295. doi: 10.3389/ti.2023.11295. eCollection 2023.
• Aguado JM, Navarro D, Montoto C, Yebenes M, de Castro-Oros I. Incidence of refractory CMV infection with or without antiviral resistance in Spain: A systematic literature review. Transplant Rev (Orlando). 2024 Jan;38(1):100804. doi: 10.1016/j.trre.2023.100804. Epub 2023 Nov 6.
• Fisher CE, Knudsen JL, Lease ED, Jerome KR, Rakita RM, Boeckh M, Limaye AP. Risk Factors and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infection in Solid Organ Transplant Recipients. Clin Infect Dis. 2017 Jul 1;65(1):57-63. doi: 10.1093/cid/cix259.
• Kampouri E, Manuel O. Preemptive therapy versus universal prophylaxis: Time for reconciliation? Transpl Infect Dis. 2023 Apr;25(2):e14014. doi: 10.1111/tid.14014. Epub 2023 Feb 3. No abstract available.
• Stern M, Hirsch H, Cusini A, van Delden C, Manuel O, Meylan P, Boggian K, Mueller NJ, Dickenmann M; Members of Swiss Transplant Cohort Study. Cytomegalovirus serology and replication remain associated with solid organ graft rejection and graft loss in the era of prophylactic treatment. Transplantation. 2014 Nov 15;98(9):1013-8. doi: 10.1097/TP.0000000000000160.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): January 30, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: July 26, 2026
• First Submitted That Met QC Criteria: August 22, 2026
• First Posted (Actual): August 26, 2026

Study Record Updates

• Last Update Posted (Actual): August 26, 2026
• Last Update Submitted That Met QC Criteria: August 22, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: CMV; solid organ transplant; Drug Resistance, Viral; antiviral resistance; refractory infection
• Additional Relevant MeSH Terms: Virus Diseases; DNA Virus Infections; Herpesviridae Infections; Infections; Cytomegalovirus Infections
• Other Study ID Numbers: 7752 (CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared. Study data are de-identified and coded using a randomly generated numeric key, in accordance with Argentine Personal Data Protection Law 25.326/00 (Habeas Data) and institutional confidentiality requirements. Access is restricted to the principal investigator, and the database will be deleted upon completion of the statistical analysis.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No