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A total of 315 patients were included in the analysis, with baseline (pre-HCT) and twice-weekly plasma specimens collected over 12 weeks post-HCT for HHV-6 testing. The patients were also followed through day 200 for mortality. Cox proportional hazards models were used to investigate the associations between HHV-6 reactivation and CMV reactivation, aGVHD, and mortality.
HHV-6 reactivation was detected in 111(35%) of the patients through 12 weeks post-HCT, with a median time to reactivation of 20 days post-HCT. This reactivation was associated with subsequent CMV reactivation (adjusted hazard ratio [aHR], 1.9, 95% confidence interval [CI], 1.3-2.8, p=0.002). Additionally, high-level HHV-6 (defined as >1000 HHV-6 DNA copies/mL) was associated with subsequent grades II to IV aGVHD (aHR, 2.4; 95% CI, 1.60-3.6, p<0.001). High level HHV-6 reactivation was also associated with nonrelapse mortality (aHR, 2.7; 95% CI, 1.2-6.3; p=0.02).
The results of this study suggests that the association between HHV-6 and mortality in HCT may be partially mediated by aGVHD. Previous clinical data suggest that HHV-6 reactivation may also cause a pro-inflammatory response that may be important in the development of aGVHD; however, Zerr and colleagues note that many complex pathways could link HHV-6 reactivation with increased complications following HCT.
In summary, HHV-6 reactivation was independently and quantitatively associated with increased risk of subsequent CMV reactivation, aGVHD, and mortality post-HCT. Given the results of this study, the authors suggest that a randomized controlled antiviral trial, which could definitively establish causality, is warranted to determine if reducing HHV-6 reactivation will reduce the incidence of these outcomes after HCT.
Zerr DM, Boeckh M, Delaney C, Martin PJ, Xie H, Adler AL, Huang ML, Corey L, Leisenring WM. 2012. HHV-6 Reactivation and Associated Sequelae after Hematopoietic Cell Transplant. Biol Blood Marrow Transplant. doi:10.1016/j.bbmt.2012.05.012