An increased awareness of diseases associated with HHV-6 infection and reactivation in both immunocompetent and immunocompromised patients has resulted in a growing interest in the evaluation of the best treatment options available for the clinical management of HHV-6 disease. However, no compound has yet been approved exclusively for the treatment of HHV-6. Thus, clinicians most often utilize the anti-cytomegalovirus (CMV) agents ganciclovir (Cytovene® IV), cidofovir (Vistide® IV), and foscarnet (Foscavir® IV) for the clinical treatment of HHV-6 (Table below). CMV (HHV-5) is a beta-herpesvirus that is closely related to both HHV-6A and HHV-6B.

Although no internationally approved guidelines currently exist for the clinical treatment of HHV-6, the International Herpesvirus Management Forum and American Society of Transplantation Infectious Disease Community of Practice have recommended the initiation of antiviral therapy in cases of HHV-6 encephalitis. Foscarnet is currently considered the preferential treatment option for HHV-6 encephalitis in patients with anemia, as the administration of ganciclovir poses an additional risk of dose-limiting hematological toxicity. Risks associated with foscarnet include renal toxicity as well as complications from catheter-related deep vein thrombosis and infection. Unlike cidofovir, foscarnet cannot be administered in a peripheral vein. Of the three compounds, an oral prodrug is currently only available for ganciclovir (Valcyte® ORAL).

Current drugs with activity against HHV-6
Drug Name
Brand Name(s)
Main Use
In Vitro Activity against HHV-6
Cross BBB?
Clinical Risks
ganciclovir (IV) valganciclovir (oral)
 Cytovene, Valcyte HCMV Moderate Yes Bone Marrow Suppression
cidofovir
 Vistide HCMV Good No (a) Renal Toxicity
foscarnet
 Foscavir HCMV Excellent Yes Renal Toxicity
artesunate
 Malartin, Artesor malaria Excellent Yes Minimal
lipid tagged cidofovir (IV)

Phase II Trials

 IV Brincidofovir(CMX001)** DNA Viruses Excellent Yes (b) Minimal (Low Dose)
“off-the-shelf” Cytotoxic T-Cell Therapy

Phase II Trials

 Viralym M AdV, BKV, CMV, EBV, HHV-6 Excellent Yes None

(a) The product insert for Vistide states that the compound does not efficiently cross the BBB, but data is limited to one unpublished case report

(b) According to Chimerix, animal studies show that there is much greater penetration to the brain and organs than with the oral formulation.

**Phase III trial underway for HCMV

Because of the many limitations discussed above, there is a great need for the development of novel antivirals to more effectively treat acute HHV-6 infections and reactivation. Several other compounds in various stages of clinical development have also shown effectiveness against HHV-6 in vitro (Table). More information regarding select compounds featured in this list can be found below.

Potential anti-HHV-6 agents of the future
Stage of Clinical Development/ Availability Compound name Developing company or Laboratory Intended use FDA approval/ development phase In vitro efficacy against HHV-6
Approved in many countries. Artesunate** Guilin Pharm. Co. (China), Saokim Ltd. (Int’l) Acute malaria CDC IND approval in the USA Very good
In pharmaceutical development
Ampligen Hemispherx Biopharma (USA) CFS Good
Cyclopropavir  Microbiotix, Inc (USA) CMV, other herpesviruses Completed Phase I Excellent
Showed efficacy in laboratory testing
Valomaciclovir

AZT-lipid-PFA

 Epiphany Biosciences (USA) VZV (Shingles); EBV (infectious mononucleosis FDA Phase IIB trial for VZV, IIA trial for EBV. Good
S2242 Hoechst (Germany) Many herpesviruses N/A Good
Arylsulfone derivatives Rega Institute (Belgium) betaherpesviruses N/A Good
ZSM Derivatives Wayne St. University of Medicine CMV and other herpesviruses N/A Moderate
BDCRB University of Michigan-Glaxo Wellcome, Inc. (USA) CMV N/A Moderate
A-5021 Ajinomoto Co, Inc. (Japan) HSV N/A Moderate
(AV-038)
a) FDA approval rating and trial stage reported by the United States’ Food and Drug Administration (FDA) as of July 2013 

**The following compounds have shown superior antiviral efficacy, and are currently either FDA approved for clinical use or in advanced stages of clinical development:

IV Brincidofovir (CMX001)
This agent is a derivative of cidofovir, modified to allow enhanced cellular permeability compared to its predecessor. This derivation increases the in vitro activity against HHV-6 by a factor of 100-fold (compared to  CDV), allowing for heightened effectiveness at sub-cytotoxic concentrations.  Phase III clinical trials of an oral agent failed because too much of the drug was absorbed in the gut, causing bleeding. It has been reintroduced in an IV formulation at a dose that is 1/10th that of the oral medication. The IV formulation has much better penetration to the organs and to the brain than the oral formulation.

ARTESUNATE
Artesunate (ART), used globally for the treatment of malaria, has recently shown excellent efficacy against HHV-6 in vitro and is currently being explored in several centers for the treatment of drug-resistant CMV infections. In addition, Artesunate also proved to be an effective treatment for HHV-6B myocarditis in a pediatric patient.

Cytotoxic T cell treatment for HHV-6

Viracyte has licensed a novel technique from Baylor College of Medicine’s Center for Cell and Gene Therapy. The Baylor group was able to generate “off the shelf” antiviral T cells for the treatment of five opportunistic viral infections, one of which was HHV-6, and this therapy has proven to be extremely effective in small trials. Their novel therapy can treat five viruses (AdV, EBV, CMV, BKV, and HHV6) representing the most frequent causes of viral morbidity and mortality in immune-compromised patients following stem cell transplantation.

This technique, called “adoptive transfer of virus-specific T cells (VSTs),” can be safe and effective, and offers many advantages over conventional antiviral treatment options because there is no toxicity and it can be used for patients infected with strains that are resistant to commonly used antivirals. Unfortunately, the cells themselves have historically been complex to prepare and limited in their antiviral range. However, after years of work that included development of an enhanced adoptive T cell immunotherapy specific to HHV-6B, as well as refining an immunotherapy technique for limiting the effects of EBV and a set of eleven viruses known to cause complications following hematopoietic stem cell transplantation (HSCT), this group’s novel approach now demonstrates the feasibility and clinical utility of rapidly generated single-culture VSTs. This therapeutic approach of isolating, treating and injecting patients with T cells may eventually prove to be the safest and most cost-effective alternative for patients with severe viral infections.

Key Resources: HHV-6 Treatment

The establishment of formal treatment guidelines for the effective clinical management of HHV-6 is desperately needed. While the significance of HHV-6 is becoming more clearly defined in some clinical settings (CNS infections; solid organ transplant (SOT) patients; and HSCT), the specific role of HHV-6 infection or reactivation remains to be fully established. Large-scale studies are needed to obtain a more complete understanding of the clinical impact of HHV-6A and HHV-6B, and to identify more optimal therapies to manage these emerging viruses.
The HHV-6 Foundation would like to thank Dr. Lieve Naesens and Dr. Jose Montoya for their assistance in the preparation of this summary.