Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis

Abstract

Over the past 25 years, several randomized controlled trials have investigated the efficacy of different antiviral agents for cytomegalovirus (CMV) prophylaxis in allogeneic hematopoietic cell transplantation. We performed a systematic literature review, conventional meta-analysis, and network meta-analysis using a random-effects model and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) as effect estimates. Fifteen randomized controlled trials were identified, including 7 different antiviral agents: acyclovir, ganciclovir, maribavir, brincidofovir, letermovir, valacyclovir, and vaccine. Twelve trials used placebo as comparator while 3 trials compared different antiviral agents. We found evidence for CMV disease and infection being significantly reduced by antiviral prophylaxis, with an RR of .66 (95% CI, .48 to .90) and .63 (95% CI, .50 to .79). Across the network, ganciclovir showed the best relative efficacy for CMV disease while letermovir provided first rank of being the best option for CMV infection. The risk for death was not significantly influenced by antiviral prophylaxis in the meta-analysis, with an RR of .92 (95% CI, .78 to 1.08), as well as in the network meta-analysis. In terms of safety, letermovir was at least similar in comparison with placebo and most agents while both letermovir and acyclovir showed significantly reduced risk for serious adverse events compared with ganciclovir, with RRs of .55 (95% CI, .30 to 1.00) for letermovir and .63 (95% CI, .42 to .93) for acyclovir. With a probability of 81%, letermovir appears to be the best option in terms of safety. Future randomized head-to-head comparisons are needed to evaluate the definite efficacy and safety of different prophylactic strategies.

Optimized EBMT transplant-specific risk score in myelodysplastic syndromes after allogeneic stem-cell transplantation

“…19–21 A recent evidence synthesis of the efficacy and safety of different prophylactic strategies for CMV highlighted inconclusive results in terms of survival while CMV disease and infection could be significantly reduced using antiviral agents. 20 Furthermore, it is unclear whether different prophylactic agents for graft- versus -host disease increase the risk for CMV infection or disease after transplantation. Aggregated evidence did not show an increased risk for CMV reactivation in randomized trials on antithymocyte globulin, which was given to 46% of our EBMT cohort, in comparison with standard prophylaxis using cyclosporine and methotrexate or tacrolimus.…”

Cost-effectiveness of letermovir as cytomegalovirus prophylaxis in adult recipients of allogeneic hematopoietic stem cell transplantation in Hong Kong

“…While these agents are effective in the prevention of CMV reactivation, their use is associated with significant toxicity and has not been shown to be superior to the pre-emptive strategy. [19][20][21] . These approaches have reduced the burden of CMV disease and its associated morbidity and mortality 19,22 .…”

“…[19][20][21] . These approaches have reduced the burden of CMV disease and its associated morbidity and mortality 19,22 . However, the burden of CMV infection remains prominent, and pre-emptive therapy entails hospitalization, significant adverse effects, and considerable expenses 23,24 .…”

Exploring failure of antimicrobial prophylaxis and pre-emptive therapy for transplant recipients: a systematic review

“…In addition, some reasons were not clarified, for example physician and patient discretion were combined in two of the included studies. A systematic review published in 2018 explored the efficacy and safety of CMV prophylaxis; adverse events and breakthrough infections were addressed, however the authors did not explicitly report additional information why patients stopped within these studies 54. Similarly, in a PCP prophylaxis systematic review, the authors described adverse events as reason for discontinuation while not mentioning adherence, resistance or patients’ choice 14…”