Treatment of Adenovirus (AdV) Infection in Allogeneic Hematopoietic Cell Transplant (HCT) Patients (pts) with Brincidofovir: 24 Week Interim Results from the AdVise Trial

Background: AdV infection is an important cause of morbidity and mortality after HCT, with 50-80% mortality reported for disseminated disease, generally in the first 60 d after diagnosis. Brincidofovir (BCV) is an investigational antiviral with high potency in vitro against all AdV subtypes. Herein we describe outcomes in 158 HCT pts who received BCV for AdV.  Methods: Pediatric (ped, <18 y) and adult HCT pts were treated with oral BCV 100 mg twice weekly (BIW) for 12 wks; pts <50 kg received 2 mg/kg BIW. Cohort A had localized AdV infection or asymptomatic viremia (n=66); Cohort B had disseminated disease (n=92).  Results: Median BCV duration was 81 days in peds (n=100) and 47 days in adults (n=58). 92% of Cohort B and 62% of Cohort A had baseline AdV viremia; baseline AdV DNA was >4 log c/mL in 63% and 23%. Prior IV cidofovir use was 44%.

Table:  Virologic Response in Viremic Pts

	Peds		Adults
	Cohort A N=27	Cohort B N=51	Cohort A N=14	Cohort B N=34
≥2 log decline or undetectable (UND) plasma AdV at Wk4	24 (89%)	42 (82%)	11 (73%)	20 (58%)
UND plasma AdV on study	23 (85%)	39 (77%)	7 (50%)	13 (38%)
Median time (days) to UND plasma AdV (95% CI)	14 (5, 23)	22 (15, 36)	43 (8, NE)	NE (5, NE)
NE: not estimable. Lower limit of detection 100 c/mL.

Among pts with baseline CD4 counts <50 cells/uL, 55% in Cohort A and 52% of Cohort B had ≥2 log decline or UND AdV at Wk4.

All-cause mortality was lower in Cohort A than B, and in peds vs. adults. In Cohort A AdV-associated mortality through 90 d/24 wks was 5%/9% in peds, 4%/4% in adults; in Cohort B, rate was 11%/14% in peds, 40%/46% in adults. In Cohort B, 35% of adults and 55% of peds who were alive at Wk4 responded (UND plasma AdV @ Wk4); 74% of peds responders and 44% of adult responders survived to Wk24. Survival was lower among peds (53%) and adult (12%) non-responders (p=0.004 in Cox model including age grp). Prior IV CDV did not impact outcome. BCV was discontinued due to AEs in 20% of peds and 29% of adults; GI AEs were most common reason (5% and 14%).  Conclusion: Rapid declines in AdV viral load were observed on BCV, even in HCT pts with low CD4 counts. Peds pts had lower overall and AdV-associated mortality. In pts with disseminated disease, virologic response at Wk4 was correlated with overall survival. These data support continued development of BCV as the first potential therapeutic for AdV.