In this issue of Blood, Hill et al used a post hoc analysis of a randomized, placebo-controlled trial of brincidofovir (BCV) for prophylaxis against cytomegalovirus (CMV) to study the effect of this drug against human herpesvirus 6B (HHV-6B).1  BCV is a lipid conjugate of cidofovir, which can be given orally and IV and has a better safety profile than cidofovir. BCV has in vitro activity against HHV-6B. It has been studied as prophylaxis against CMV and treatment of adenovirus infections, the latter primarily in children undergoing high-risk allogeneic stem cell transplants.

In the study by Hill et al, BCV was given orally twice weekly until 14 weeks after hematopoietic stem cell transplantation (HSCT). The authors selected patients, who started study therapy early after HSCT and who had received at least 6 doses of BCV. The main findings of the study were that patients receiving BCV were less likely to reactivate HHV-6B and that they had lower viral loads. The effect was strongest in patients with risk factors for developing viral infections, including CMV and HHV-6B. Furthermore, the authors found that rash was reported less frequently in patients receiving BCV despite there being more acute graft-versus-host disease (GVHD) grades II to IV in the BCV-treated group. There was no difference in HHV-6–associated disease entities such as encephalitis and pneumonia, but the power of the study to detect any such effects was very low due to the sample size.

The role of HHV-6 as a clinically important virus after allogeneic HSCT remains murky despite several studies performed over the last couple of decades. There is no doubt that HHV-6 is a cause of encephalitis, which can be fatal and, if the patient survives, frequently results in long-term sequelae.2-4  Cohort studies have implicated HHV-6 in the development of acute GVHD grades II to IV, pneumonia, and bone marrow suppression, especially platelet recovery. HHV-6 has also been associated with increased mortality after allogeneic HSCT.5-8  Despite the reports of these complications associated with HHV-6 replications, HHV-6B in blood is not routinely monitored at many transplant centers, likely due to the lack of effective therapy. The efficacy of antiviral therapy has been difficult to assess despite HHV-6 sensitivity to several drugs in vitro, including ganciclovir, foscarnet, and cidofovir. Controlled studies assessing antiviral drugs’ effect on HHV-6 measured as either viral load or disease manifestations have not been conducted. Further complicating the picture, HHV-6 can be integrated in the genome, making interpretation of polymerase chain reaction results difficult in some patients.

The study by Hill et al is interesting for several reasons. First, it can be seen as proof of concept that BCV can inhibit HHV-6B replication, reducing the plasma viral load below the level where the risk for the most severe complication, namely encephalitis, increases.2,9  Second, the authors found a reduction in the frequency of patients developing rash in the BCV-treated group, whereas the proportion of patients diagnosed with GVHD grades II to IV was higher in the BCV group. This apparent inconsistency was likely because the rash was directly caused by HHV-6B itself as it is well known that the virus causes exanthema subitem in small children. On the other hand, gastrointestinal toxicity probably caused by BCV was likely interpreted as GVHD.

What will be the next steps? Clinical development of oral BCV has been discontinued while development of the IV form is ongoing. It would be logical to study IV BCV as a possible preventive agent for HHV-6B encephalitis, the most severe manifestation of infection, although the relative rarity of this entity will make such studies challenging.

Conflict-of-interest disclosure: P.L. declares no competing financial interests.

REFERENCES

1.
Hill
JA
,
Nichols
WG
,
Marty
FM
, et al
.
Oral brincidofovir decreases the incidence of HHV-6B viremia after allogeneic HCT
.
Blood
.
2020
;
135
(
17
):
1447
-
1451
.
2.
Zerr
DM
,
Gooley
TA
,
Yeung
L
, et al
.
Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients
.
Clin Infect Dis
.
2001
;
33
(
6
):
763
-
771
.
3.
Ogata
M
,
Satou
T
,
Kadota
J
, et al
.
Human herpesvirus 6 (HHV-6) reactivation and HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: a multicenter, prospective study
.
Clin Infect Dis
.
2013
;
57
(
5
):
671
-
681
.
4.
Scheurer
ME
,
Pritchett
JC
,
Amirian
ES
,
Zemke
NR
,
Lusso
P
,
Ljungman
P
.
HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis
.
Bone Marrow Transplant
.
2013
;
48
(
4
):
574
-
580
.
5.
Zerr
DM
,
Corey
L
,
Kim
HW
,
Huang
ML
,
Nguy
L
,
Boeckh
M
.
Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation
.
Clin Infect Dis
.
2005
;
40
(
7
):
932
-
940
.
6.
Phan
TL
,
Carlin
K
,
Ljungman
P
, et al
.
Human herpesvirus-6B reactivation is a risk factor for grades II to IV acute graft-versus-host disease after hematopoietic stem cell transplantation: a systematic review and meta-analysis
.
Biol Blood Marrow Transplant
.
2018
;
24
(
11
):
2324
-
2336
.
7.
Cone
RW
,
Hackman
RC
,
Huang
ML
, et al
.
Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation
.
N Engl J Med
.
1993
;
329
(
3
):
156
-
161
.
8.
Hill
JA
,
Vande Vusse
LK
,
Xie
H
, et al
.
Human herpesvirus 6B and lower respiratory tract disease after hematopoietic cell transplantation
.
J Clin Oncol
.
2019
;
37
(
29
):
2670
-
2681
.
9.
Ogata
M
,
Satou
T
,
Kawano
R
, et al
.
Plasma HHV-6 viral load-guided preemptive therapy against HHV-6 encephalopathy after allogeneic stem cell transplantation: a prospective evaluation
.
Bone Marrow Transplant
.
2008
;
41
(
3
):
279
-
285
.