Oral Brincidofovir Decreased HHV-6 Viremia in Hematopoietic Cell Transplant Recipients: Results from the Suppress Study

Abstract

Introduction Human herpesvirus 6B (HHV-6) is detected in plasma in ∼40% of allogeneic hematopoietic cell transplant (HCT) recipients and ∼75% of cord blood recipients. HHV-6 viremia, particularly at levels >104 copies/mL, is associated with increased risk for HHV-6 encephalitis. Ganciclovir and foscarnet have antiviral activity against HHV-6, but studies of pre-emptive or prophylactic treatment have not been successful in preventing HHV-6 encephalitis. Prophylaxis for HHV-6 has never been studied in a randomized trial. Brincidofovir (BCV, CMX001) has potent in vitro activity against HHV-6 (EC50=0.007 µM), and unlike cidofovir, has good CNS penetration. Objectives In vivo activity of BCV against HHV-6 has not been demonstrated. We tested plasma from participants in the SUPPRESS clinical trial to explore the potential of BCV to prevent HHV-6 viremia. Methods SUPPRESS was a randomized, double-blind, placebo (PBO)-controlled trial of oral BCV for cytomegalovirus (CMV) prophylaxis after allo-HCT. 452 adult CMV-seropositive HCT recipients without CMV viremia at screening were randomized 2:1 to receive BCV or PBO twice-weekly until week 14 post-HCT. We selected subjects who were randomized within 2 weeks of allo-HCT, who did not have HHV-6 viremia at baseline, and who received at least 6 doses of BCV or PBO within the first 3 weeks of randomization for HHV-6 testing. Plasma samples from the first six weeks post-HCT were tested for HHV-6 with quantitative PCR (Viracor Eurofins, Lee's Summit, MO). We compared HHV-6 viremia between subjects who received BCV and those who received PBO using the Kaplan-Meier method, log rank test, and Cox proportional hazards model. Results 92 subjects in the BCV group and 61 in the PBO group met criteria for inclusion: 64% were male, 84% were white, and median age was 57 years (range: 18-76). 6% of subjects received cord blood grafts, 5% had haploidentical donors, and 8% had mismatched donors. 41% had ex vivo T-cell depletion or received serotherapy with antithymocyte globulin or alemtuzumab. Baseline characteristics were balanced between groups. 15% of BCV subjects vs. 31% of PBO subjects had detectable HHV-6 viremia within 6 weeks after HCT. The cumulative incidence of HHV-6 viremia was significantly lower in BCV subjects (Figure 1). Two subjects (2%) in the BCV group had HHV-6 viremia >103 copies/mL compared to 7 (11%) in the PBO group (Figure 2). In the study overall, no subjects in the BCV group and one in the PBO group developed HHV-6 encephalitis. Conclusion BCV reduced the incidence of detectable HHV-6 viremia in HCT recipients enrolled in a randomized, placebo-controlled clinical trial. BCV prophylaxis could prevent the morbidity and mortality associated with HHV-6 in HCT recipients.