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Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic-Cell Transplantation: a Systematic Review and Meta-Analysis
Gagelmann, N., Ljungman, P., Styczynski, J., Kroger, N.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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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 (RR) with corresponding 95% confidence intervals (CI) as effect estimates. Fifteen randomized controlled trials were identified, including seven different antiviral agents: acyclovir, ganciclovir, maribavir, brincidofovir, letermovir, valacyclovir, and vaccine. Twelve trials used placebo as comparator while three trials compared different antiviral agents. We found evidence for CMV disease and infection being significantly reduced by antiviral prophylaxis with RR of 0.66 (95% CI, 0.48-0.90) and 0.63 (95% CI, 0.50-0.79). 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 a RR of 0.92 (95%CI, 0.78-1.08) 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 0.55 (95% CI, 0.30-1.00) for letermovir and 0.63 (95% CI, 0.42-0.93) 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.
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Human Herpesvirus-6B (HHV-6B) Reactivation is a Risk Factor for Grade 2-4 Acute Graft-Versus-Host Disease (aGVHD) after Hematopoietic Stem Cell Transplantation (HCT): a Systematic Review and Meta-Analysis
Phan, T. L., Carlin, K., Ljungman, P., Politikos, I., Boussiotis, V., Boeckh, M., Shaffer, M. L., Zerr, D. M.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
BACKGROUND/OBJECTIVE Graft-versus-host disease (GVHD) is an important cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Many studies have suggested that HHV-6B plays a role in acute GVHD (aGVHD) following HCT. Our objective was to systematically summarize and analyze evidence regarding HHV-6B reactivation and development of aGVHD. METHODS PubMed and EMBASE databases were searched using terms for HHV-6, HCT, and aGVHD, yielding 865 unique results. Case reports, reviews, articles focusing on inherited chromosomally integrated HHV-6, poster presentations, and articles not published in English were excluded. The remaining 467 papers were reviewed for the following requirements: (i) a statistical analysis of HHV-6B reactivation and aGVHD was described, (ii) HHV-6 reactivation was defined by PCR, and (iii) blood (plasma, serum or PBMCs) was used for HHV-6B PCR. Data were abstracted from publications that met these criteria (n=33). Publications were assigned to one of 3 groups: (1) HHV-6B reactivation was analyzed as a time-dependent risk factor for subsequent aGVHD (n=14), (2) aGVHD analyzed as a time-dependent risk factor for subsequent HHV-6B reactivation (n=1), and (3) analysis without temporal specification (n=18). RESULTS A statistically significant association (p<0.05) between HHV-6B reactivation and aGVHD was observed in 10/14 (71%) of studies in Group 1, 0/1 (0%) studies in Group 2, and 8/18 (44.4%) studies in Group 3. Of the 14 studies that analyzed HHV-6B as a risk factor for subsequent aGVHD, eleven performed a multivariate analysis and reported a hazard ratio (HR), which reached statistical significance in 9 of these studies. Meta-analysis of these 11 studies demonstrated a statistically significant association between HHV-6B and subsequent grade 2-4 aGVHD (HR 2.65 [95% CI 1.89-3.72], p<0.001). CONCLUSION HHV-6B reactivation is associated with aGVHD, and when studies have a temporal component to their design, HHV-6B reactivation is associated with subsequent aGVHD. Further research is needed to investigate whether antiviral prophylaxis reduces incidence or severity of aGVHD.