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Clinical Trial
. 2024 Dec 16;230(6):e1287-e1298.
doi: 10.1093/infdis/jiae287.

Cytomegalovirus Antiviral Resistance Among Kidney Transplant Recipients in a Phase 3 Trial of Letermovir vs Valganciclovir Prophylaxis

Julie M Strizki  1 , Tracy L Diamond  1 , Valerie L Teal  1 , Christopher L Gilbert  1 , Weiwen Wang  1 , Nicole Stauffer  1 , Barbara A Haber  1
Affiliations
Clinical Trial

Cytomegalovirus Antiviral Resistance Among Kidney Transplant Recipients in a Phase 3 Trial of Letermovir vs Valganciclovir Prophylaxis

Julie M Strizki et al. J Infect Dis. .

Abstract

Background: In a phase 3 trial, letermovir was noninferior to valganciclovir for cytomegalovirus (CMV) disease prophylaxis in kidney transplant recipients who were CMV-seronegative and received kidneys from donors who were CMV-seropositive. Genotypic antiviral resistance and CMV glycoprotein B (gB) genotype are reported.

Methods: Plasma samples with detectable CMV DNA were sequenced for the presence of known letermovir and valganciclovir resistance-associated amino acid substitutions (RASs) encoded by CMV gene regions (UL51, UL54, UL56, UL89, UL97) and prevalence of gB (UL55) genotypes (gB1-gB5).

Results: Among participants, 84 of 292 (letermovir) and 93 of 297 (valganciclovir) had evaluable data for ≥1 gene target. Letermovir RASs were not detected in participants who received letermovir prophylaxis; however, 3 had valganciclovir RASs (pUL97). Twelve participants who received valganciclovir prophylaxis had valganciclovir RASs (pUL54, pUL97), and 1 who did not receive letermovir during the trial had letermovir RASs (pUL56). All but 1 participant responded to valganciclovir treatment irrespective of breakthrough CMV DNAemia or frequency of RASs. gB1 was the most frequent genotype across all participants and subgroups.

Conclusions: Letermovir RASs were not detected with letermovir prophylaxis, supporting a low risk for development of resistance in kidney transplant recipients who were CMV-seronegative and received kidneys from donors who were CMV-seropositive.

Clinical trials registration: ClinicalTrials.gov, NCT03443869; EudraCT, 2017-001055-30.

Keywords: cytomegalovirus; kidney transplant recipient; letermovir; prophylaxis; resistance.

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Conflict of interest statement

Potential conflicts of interest. All authors are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA who may own stock and/or hold stock options in Merck & Co, Inc, Rahway, NJ, USA. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Cytomegalovirus (CMV) DNA profiles and resistance-associated amino acid substitutions (RASs) in participants who completed letermovir prophylaxis. Bars along the top represent CMV antivirals, and the length of each bar indicates the duration; gaps reflect periods when CMV antivirals were not administered. Text labels adjacent to selected symbols indicate specific RASs; the percentage represents the frequency of next-generation sequencing reads in the CMV DNA sequence encoding the RAS, with percentages ≥20% bolded. formula image letermovir prophylaxis; formula image valganciclovir treatment. Symbols reflect the outcome from genotypic analysis: formula image sample not collected; formula image RAS detected; formula image sequencing failed. *Confirmed CMV disease.
Figure 2.
Figure 2.
Cytomegalovirus (CMV) DNA profiles in participants with resistance-associated amino acid substitutions (RASs) detected early (within 2 months) after or near completion of valganciclovir prophylaxis. Bars along the top represent CMV antivirals, and the length of each bar indicates the duration; gaps reflect periods when CMV antivirals were not administered. Text labels adjacent to selected symbols indicate specific RASs; the percentage represents the frequency of next-generation sequencing reads in the CMV DNA sequence encoding the RAS, with percentages ≥20% bolded. formula image valganciclovir prophylaxis; formula image valganciclovir/ganciclovir treatment; formula image foscarnet treatment. Symbols reflect the outcome from genotypic analysis: formula image sample not collected; formula image RAS detected; formula image RAS not detected; formula image sequencing failed. *Confirmed CMV disease.
Figure 3.
Figure 3.
Cytomegalovirus (CMV) DNA profiles in participants with resistance-associated amino acid substitutions (RASs) detected later (>2 months) after completion of valganciclovir prophylaxis. Bars along the top represent CMV antivirals, and the length of each bar indicates the duration; gaps reflect periods when CMV antivirals were not administered. Text labels adjacent to selected symbols indicate specific RASs; the percentage represents the frequency of next-generation sequencing reads in the CMV DNA sequence encoding the RAS, with percentages ≥20% bolded. formula image valganciclovir prophylaxis; formula image valganciclovir/ganciclovir treatment. Symbols reflect the outcome from genotypic analysis: formula image sample not collected; formula image RAS detected; formula image RAS not detected; formula image sequencing failed. *Confirmed CMV disease.
Figure 4.
Figure 4.
Cytomegalovirus (CMV) DNA profiles and resistance-associated amino acid substitutions (RASs) detected in participants who did not complete valganciclovir prophylaxis. Bars along the top represent CMV antivirals, and the length of each bar indicates the duration; gaps reflect periods when CMV antivirals were not administered. Text labels adjacent to selected symbols indicate specific RASs; the percentage represents the frequency of next-generation sequencing reads in the CMV DNA sequence encoding the RAS, with percentages ≥20% bolded. formula image valganciclovir prophylaxis; formula image valganciclovir/ganciclovir treatment; formula image letermovir treatment; formula image foscarnet treatment. Symbols reflect the outcome from genotypic analysis: formula image sample not collected; formula image RAS detected; formula image RAS not detected. *Confirmed CMV disease. †RAS not detected upon repeat next-generation sequencing.
See this image and copyright information in PMC

References

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