Researchers at the University of Washington demonstrate a reduction in the incidence and Viral load of HHV-6B reactivation in allogeneic HCT patients who received prophylactic oral brincidofovir in a post hoc analysis of a randomized controlled trial (SUPPRESS).
In this post-hoc analysis (Hill 2020) of a randomized, double-blind, placebo-controlled phase 3 trial evaluating oral brincidofovir for CMV prophylaxis (Marty 2019), researchers demonstrated a decreased incidence of HHV-6B plasma detection through day +42 post-HCT in patients who received oral brincidofovir compared to placebo (14.2% vs. 32.4%). In their adjusted Cox model, brincidofovir was associated with a lower hazard for HHV-6B plasma detection (HR 0.40, 95% CI 0.20-0.80).
Brincidofovir is a lipid conjugate of cidofovir with a distinct safety profile from other commonly used anti-HHV-6 antivirals (e.g. foscarnet, ganciclovir) such as lack of nephrotoxicity. In this post-hoc analysis (Hill 2020), researchers obtained samples from CMV-seropositive alloHCT patients enrolled in the SUPPRESS trial who received oral brincidofovir twice weekly until week 14 post-HCT. Patients who were randomized within 2 weeks of HCT and received at least 6 doses of brincidofovir or placebo within the first 3 weeks after randomization were included. Plasma samples collected through the first 6 weeks post-HCT from these patients were tested for HHV-6B with quantitative PCR. Patients with HHV-6B detection at baseline randomization were excluded. Patients were considered high-risk for HHV-6B reactivation if they received cord blood (Scheurer 2013), ex-vivo T cell-depleted grafts (Sisinni 2018), grafts from unrelated, mismatched, haploidentical donors, anti-thymocyte globulin or alemtuzumab, or were being treated with prednisone ≥1mg/kg/day (Phan 2018).
Of the 452 randomized patients in the SUPPRESS trial, 98 patients who received brincidofovir and 64 who received placebo met inclusion criteria for this study. Median duration of study drug administration through week 6 post-HCT was 32 days in the brincidofovir arm and 30 days in the placebo arm; 89% of the patients remained on brincidofovir by week 6 compared to 70% who remained on placebo by week 6. The cumulative incidence of HHV-6B plasma detection by week 6 post-HCT was lower among patients who received brincidofovir (14.2%) compared to those who received placebo (32.4%). Additionally, patients who received brincidofovir had a lower viral loads: only 2 (2%) patients in the brincidofovir arm had >1,000 copies/mL plasma compared to 7 (11%) patients in the placebo arm. There were 69 (75%) patients in the brincidofovir arm who were considered high-risk for HHV-6B reactivation vs. 39 (64%) patients in the placebo arm; brincidofovir appeared to have a greater effect on preventing HHV-6 reactivation among these high-risk patients (HR 0.39, 95% CI 0.17-0.89).
Rashes occurred less often in patients who received brincidofovir (9%) compared to placebo (26%, p=0.006). There was no difference in the in the incidence of pneumonia (1 patient on brincidofovir vs. 2 patients on placebo) or encephalitis (0 patients on brincidofovir and 1 patient on placebo). The limited number of these events precluded statistical analysis. Past studies have shown that prophylactic doses of foscarnet (90mg/kg/day) have not effectively prevented HHV-6 encephalitis (Ogata 2018).
HHV-6B reactivation has been associated with increased risk of developing subsequent grade 2-4 aGVHD (Phan 2018). In the current study, during the first 6 weeks post-HCT, grade 2-4 aGVHD was reported in 37 (40%) patients receiving brincidofovir (median onset 28 days) and 6 (10%) patients receiving placebo (median onset 35 days).
Unfortunately, much of oral brincidofovir is absorbed in the gut (Quenelle 2010). For this reason, patients who received brincidofovir had a high degree of GI toxicity which may have been misinterpreted as aGVHD. This resulted in higher steroid administration and adverse consequences. For that reason, the investigators recommend using the IV formulation in future HHV-6 studies. IV brincidofovir has a higher organ and CNS penetration.
Read the study here: Hill 2020