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K.N. Ward et al.
from HSCT recipients previously diagnosed with idio- pathic pneumonia syndrome. HHV-6 was the most com- mon pathogen (29% of cases) identified, and it was the only pathogen in approximately half of these.63 However, the clinical significance of this finding remains to be determined.
Although there are many reports of HHV-6B-associated hepatitis after liver transplantation, this has only been well documented in two cases post-HSCT,64,65 both of which describe acute hepatitis successfully treated with ganciclovir. HHV-6B DNA was demonstrated in hepatic tissue by immunohistochemistry.
• In suspected end-organ disease other than failed engraftment or encephalitis, tissue from the affected organ should be tested for HHV-6 infection by culture, immunochemistry, in situ hybridization or reverse tran- scription PCR for mRNA.
• PCR for HHV-6 DNA in tissue is not recommended for documentation of HHV-6 disease.
• Other likely infectious or non-infectious causes must be excluded.
• CIHHV-6 in donor and recipient should be excluded.
Human herpesvirus 6B and cytomegalovirus reactivation
Human herpesvirus 6B reactivation has been associated with an increased risk of subsequent CMV reactivation and disease post-HSCT,45,66 although this was not replicat- ed in another study.67 One study suggests that HHV-6 reactivation may indicate cellular immunosuppression which also predisposes to CMV reactivation.68 In vitro studies of HHV-6 reactivation demonstrate that HHV-6B infection might contribute to CMV reactivation through inhibition of IL-12 production.69,70
Human herpesvirus 6B - acute graft-versus-host disease and increased all-cause mortality
A well-designed study established an association between HHV-6B reactivation and subsequent acute GvHD.71 A meta-analysis of 11 such studies demonstrat- ed a statistically significant association between HHV-6B and subsequent grade II-IV acute GvHD (HR: 2.65; 95%CI: 1.89-3.72; P<0.001).72
Human herpesvirus 6B reactivation has also been asso- ciated with increased all-cause mortality post- HSCT.45,46,73,74 However, whether HHV-6B directly or indi- rectly impacts on mortality in the absence of clinically apparent end-organ disease remains unclear.
Treatment strategies
Antiviral drugs and immunotherapy
Ganciclovir, foscarnet, and cidofovir inhibit HHV-6 replication in vitro.75 Whilst in vitro studies support the potential for HHV-6 to develop resistance to the above antiviral agents, very few case reports have described the emergence of drug-resistant isolates, specifically to ganci- clovir, and after lengthy exposure in the clinical setting.76- 79 Additionally, the use of valganciclovir or ganciclovir treatment for CMV disease did not result in the emer- gence of drug-resistant HHV-6 mutants in a large prospec- tive trial of solid organ transplant patients.80
New treatment modalities for HHV-6 are needed due to the nephrotoxic and myelosuppressive properties of the
available agents. Brincidofovir (or CMX-001) has high in vitro activity against HHV-6 species81 but has significant gastrointestinal toxicity;82 an intravenous formulation under development may be better tolerated.83 However, this drug is not currently available for clinical use. Adoptive immunotherapy with virus-specific T cells is an exciting new therapeutic approach for HHV-6.84,85 This approach appears to be safe and potentially effective in small, uncontrolled studies.
Prevention of human herpesvirus 6B encephalitis
Human herpesvirus 6B DNA screening during the high- risk period post-HSCT is impractical as HHV-6 reactiva- tion often coincides with the onset of disease.48 Effective pre-emptive or prophylactic strategies have not been identified. Three prospective, non-randomized studies of prophylactic foscarnet (pre- or post-engraftment) did not significantly lower the incidence of encephalitis.86-88 Similarly, two prospective, non-randomized studies of pre-emptive ganciclovir or foscarnet did not reduce the incidence of HHV-6B encephalitis.89,90 Failure of these approaches may be a result of inadequate dosing due to concerns about toxicity and resultant insufficient drug penetration into the CSF. Thus, routine HHV-6 DNA screening is not recommended for pre-emptive or pro- phylactic therapy, in any context.
• Routine screening of HHV-6 DNA in blood post- HSCT is not recommended (DIIu)
• Anti-HHV-6 prophylactic or pre-emptive therapy is not recommended for the prevention of HHV-6B reactiva- tion or encephalitis post-HSCT (DIIu)
Treatment of human herpesvirus 6B encephalitis
Zerr et al.91 demonstrated a response of HHV-6 to gan- ciclovir or foscarnet as measured by DNA in the CSF or serum of allogeneic HSCT patients. Ljungman et al.92 reported reductions in the HHV-6 load in saliva in patients receiving ganciclovir for pre-emptive therapy of CMV. Vu et al.93 described positive responses in 4 of 5 patients treated with foscarnet.
On the basis of the above results, foscarnet or ganci- clovir were recommended for treatment of HHV-6 encephalitis post-HSCT.94 Since then a substantial amount of additional evidence supports the use of ganci- clovir and foscarnet. Hill et al.49 treated 18 patients with HHV-6 PALE with foscarnet 180 mg/kg/day and symp- toms improved in most. Schmidt-Hieber et al.95 reported a response rate of 63% with either foscarnet or ganciclovir therapy for HHV-6 encephalitis. More recently, data comparing the use of ganciclovir with foscarnet in Japanese patients36 showed response rates of neurological symptoms were 83.8% and 71.4% with foscarnet monotherapy and ganciclovir monotherapy, respectively (P=0.10, Fisher’s exact test). Full-dose therapy with fos- carnet (≥180 mg/kg) or ganciclovir (≥10 mg/kg) was asso- ciated with a better response rate than treatment with lower doses (foscarnet, 93% vs. 74%, P=0.044; ganci- clovir, 84% vs. 58%, P=0.047). The response rate of ten patients receiving combination therapy with various doses of foscarnet and ganciclovir was 100%. However, the small sample size limits conclusions regarding whether combination therapy is superior to monothera- py, and drug toxicity is an important consideration. Death from any cause within 30 days after development of HHV-6 encephalitis was significantly lower in patients
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haematologica | 2019; 104(11)