Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

Abstract

On November 7, 2017, the US Food and Drug Administration approved the use of letermovir (LMV) for prophylaxis of cytomegalovirus (CMV) infection in adult CMV‐seropositive allogeneic stem cell transplant recipients. After 6 years of use, a large body of real‐world experience has been accumulated that validates the Phase III clinical trial results, in which LMV was shown to significantly reduce the risk of clinically significant CMV infection—defined as CMV end‐organ disease or CMV DNAemia requiring pre‐emptive antiviral therapy (PET)—and increase survival up to Week 24 after treatment inception. Notwithstanding, several issues still need to be settled, thus further investigation is required. First, since viral DNA may accumulate as a result of LMV‐driven abortive CMV infection, what is the optimal viral load threshold in the blood that would prompt LMV prophylaxis interruption and PET inception? Should this be adapted to the patient's risk? Second, what is the impact of LMV prophylaxis on the reconstitution of functional CMV‐specific T‐cell responses? Would it be a wise approach to individually tailor the duration of LMV treatment according to the number of peripheral blood CMV‐specific T cells at the end of regular prophylaxis? Third, how frequently do LMV‐resistant strains arise while patients are on LMV prophylaxis and how could this be minimized? Here, we discuss the literature addressing these topics.

Letermovir use may impact on the Cytomegalovirus DNA fragmentation profile in plasma from allogeneic hematopoietic stem cell transplant recipients

“…First, we provide evidence suggesting that our experimental approach may reliably identify self-resolving (abortive) breakthrough CMV DNAemia episodes occurring in LMV patients; this, when low CMV DNA thresholds are used for triggering PET, would allow discrimination between bona fide and abortive CMV infection, thus avoiding unnecessary LMV interruption. [18][19][20] Further investigations are needed to confirm our findings and determine whether this strategy may crystallize in the design of a commercial PCR assay for the above purpose.…”

“…LMV targets the terminase complex, which excises concatemeric viral DNA to generate full‐length monomeric genomes that can be encapsidated, but does not prevent CMV DNA replication 17 . Breakthrough CMV DNAemia may occur in patients under LMV prophylaxis and may either truly reflect active CMV infection potentially tributary of PET or, more commonly, an abortive self‐resolving infection episode that would not require LMV cessation and subsequent inception of PET 18–20 . Discrimination between these two possibilities is unfeasible when low CMV DNA thresholds are used for triggering PET 18 .…”

“…17 Breakthrough CMV DNAemia may occur in patients under LMV prophylaxis and may either truly reflect active CMV infection potentially tributary of PET or, more commonly, an abortive self-resolving infection episode that would not require LMV cessation and subsequent inception of PET. [18][19][20] Discrimination between these two possibilities is unfeasible when low CMV DNA thresholds are used for triggering PET. 18 We hypothesized that, due to differences in their spatial configuration, concatemeric and monomeric CMV DNA may be fragmented differently, thus resulting in a dissimilar pattern of CMV DNA fragmentation in plasma.…”

“…[18][19][20] Discrimination between these two possibilities is unfeasible when low CMV DNA thresholds are used for triggering PET. 18 We hypothesized that, due to differences in their spatial configuration, concatemeric and monomeric CMV DNA may be fragmented differently, thus resulting in a dissimilar pattern of CMV DNA fragmentation in plasma. Here, by using a selected set of primer pairs amplifying conserved sequences within the CMV UL34, UL54, and UL80.5 genes, as these are frequently targeted by commercially available real-time PCR assays, we assessed whether the CMV DNA fragmentation pattern varies across patients, within the same patient over time, or is affected by LMV use.…”