Controlled studies are needed to determine the benefit of antiviral therapy in patients with high viral >10,000 copies/ mL.
Reactivation of latent HHV-6B occurs in 30-80% of allogeneic hematopoietic stem cell transplantation (alloHCT) patients. A literature largely of observational studies, many of them retrospective, has suggested that reactivation of the virus may increase the risk of end-organ damage, grade III/IV acute graft-versus-host disease (GVHD) and all-cause mortality.
While some cases of encephalitis and (many would agree) pneumonitis clearly result from reactivated HHV-6B following alloHCT, these cases appear to be infrequent. Moreover, the risk factors that might predict those at higher risk for these complications remain unclear, as does the value of antiviral therapy.
A new retrospective observational study from a single center—the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida—has recently been published. Of 188 consecutive adult patients receiving haploidentical alloHCT over a six-year period, 121 (64%) had at least one assessment of HHV-6 DNA, and in 48% of these patients viral DNA was detected and the viral load measured. Antiviral therapy (largely foscarnet) was started in 36% of patients with HHV-6B viremia. The treated patients had very high levels of HHV-6B reactivation, 86% with peak loads of >10,000 copies/ mL whereas only 40% of untreated patients reached high-level peak viral loads. Unfortunately, the authors did not do a subset analysis to directly compare the outcome of the 18 treated vs 15 untreated patients with peak viral loads of >10,000.
There were no differences in patient or disease characteristics between the treated and untreated (observed) groups, as shown in the table below.
The study’s findings were as follows:
- There were no differences in outcomes between treated patients with high viral loads (log1065) and observed patients with more moderate viral loads (log10 3.84)—specifically, no significant differences in the time to clearance of viremia, encephalitis, grade 3-4 GVHD, time to neutrophil or platelet engraftment, or non-relapse mortality.
- There also were no outcome differences when patients with high viral loads (54% of whom were treated with antivirals) were compared to those with lower viral loads (12% of whom were treated).
- Patients with neurological symptoms were less likely to survive than those without such symptoms (HR 4.11 P=.018)
- As would be expected, a lumbar puncture was performed more frequently in treated patients (76.2% vs. 27% P<0.001)
- Of those who received a lumbar puncture, 23% had evidence of HHV-6B in spinal fluid. However, only one of these patients had any neurological symptoms. Moreover, this patient had adrenoleukodystrophy with impaired speech and mobility that began prior to
- Of the patients treated with foscarnet, 42% suffered acute kidney injury from the therapy.
Several important limitations must be considered in drawing inferences from this study. This was a retrospective study of how patients actually were managed: there was no protocol dictating when testing for HHV-6B should be performed or when treatment should be given, or even how alloHCT should be performed. Furthermore, its relatively small size means that some of the “negative” results may reflect the fact that the study was underpowered.
Finally, the authors failed to directly compare the outcome of untreated vs treated patients with high viral loads >10,000 copies. The fact that there was no difference in outcomes between patients with high viral loads who were treated, versus patients with low viral loads who were not treated, really tells us nothing: indeed, it suggests treatment may have been effective in people with high viral loads. What is needed is a controlled study of treatment efficacy in patients with high viral loads. While IRBs might frown on such studies, the fact that a substantial fraction of people with high viral loads are not treated in routine practice—as seen in this study—reveals that many clinicians are not convinced of the value of treatment.
Read the full text: Handley 2024