Investigators were surprised that the use of the less toxic CMV specific antiviral did not result in a significant increase in HHV-6-related disease.
For many years, CMV prophylaxis in people undergoing allogeneic HCT involved use of broad-spectrum antivirals (e.g., valganciclovir, cidofovir, foscarnet). A newer alternative medication, letermovir, also is effective but less toxic, and for that reason has been used increasingly. However, unlike the broad-spectrum antivirals, letermovir has no activity against HHV-6. That is important because CMV prophylaxis typically is given at about the same time post-HCT that HHV-6 reactivation occurs. Indeed, some past studies have indicated that CMV prophylaxis with broad-spectrum antivirals also had a prophylactic effect on HHV-6-related disease.
Thus, in using letermovir, instead of broad-spectrum antivirals for CMV prophylaxis, there is the benefit of reduced toxicity—but also a theoretical increased risk of clinically significant infection with HHV-6. A team at the University of Washington led by Josh Hill studied whether this theoretical risk was borne out in practice. They conducted a retrospective cohort study of CMV-seropositive allogeneic HCT recipients during a window of time before letermovir was routinely used vs. a window of time after it was routinely used. In this uncontrolled study, use of HHV-6 testing was at the discretion of the physicians.
The study was observational, and the patient groups pre-letermovir (N=376) and post-letermovir (N=362) could have been different in important ways, such as in the incidence of acute graft-versus-host disease (GVHD). This difference, in turn, could have affected the incidence and severity of reactivated HHV-6. For this reason, multivariate statistical techniques were used to achieve balance between the cohorts.
As would be expected, the use of broad-spectrum antivirals dropped greatly as letermovir was introduced. Contrary to the authors’ hypothesis, the cumulative incidence of HHV-6 testing and detection were not significantly greater in the letermovir period. And, very reassuringly, the incidence of HHV-6 encephalitis also was not greater (0.5% vs. 0.6%, pre- vs. post-letermovir).
It is unclear why the theoretical risk of increased HHV-6-related disease did not become manifest in the post-letermovir period. It is possible that, despite using statistical techniques to eliminate unmeasured underlying differences in the patients pre- vs. post-letermovir, such differences nevertheless were present. It also is possible that CMV reactivation itself triggers reactivation of HHV-6, and that the efficacy of letermovir in preventing CMV reactivation may also have suppressed HHV-6 reactivation and subsequent disease despite letermovir having no direct antiviral activity against HHV-6. Finally, letermovir has been shown to improve immune reconstitution (by reducing myelotoxicity from broad-spectrum antivirals and CMV-induced T-cell repertoire skewing, which could have reduced the risk of HHV-6 reactivation and disease.
This retrospective observational study underlines the importance of funding a prospective study to better assess the impact of letermovir prophylaxis of CMV on the reactivation of HHV-6 and on HHV-6-related encephalitis and pneumonitis.
Read the full article: Kampouri 2023