Clinicians HHV-6 Treatment

HHV-6 Treatment

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).

Agents most commonly used for the clinical treatment of HHV-6

Drug Name Brand Name(s)a Structure Clinical Risksa
Ganciclovir, Valganciclovir Cytovene, Valcyte Nucleoside analogue Bone Marrow Suppression
Cidofovir Vistide Nucleotide analogue Renal Toxicity
Foscarnet Foscavir Pyrophosphate analogue Renal Toxicity
  a) As reported by the United States’ Food and Drug Administration (FDA)

 

Because of these limitations, 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 for (non-related) clinical use Artesunate* CDC (USA), Guilin Pharm. Co. (China), Saokim Ltd. (Int’l) Acute malaria WHO international approval, CDC IND approval in the USA Very good
In active pharmaceutical development CMX001* Chimerix, Inc. (USA) CMV, adenovirus, and smallpox FDA Fast-Track Approval Excellent
Valomaciclovir* Epiphany Biosciences (USA) VZV (shingles);  EBV (infectious mononucleosis) FDA Phase IIB trials for VZV completed; Undergoing Phase IIA trials for EBV  Very good
Ampligen Hemispherx Biopharma (USA) infectious agents associated with ME/CFS FDA CR letter issued Good
Cyclopropavir  Microbiotix, Inc (USA) CMV Undergoing Phase 1 clinical development Good
Showed efficacy in laboratory testing MCP Analogs Microbiotix, Inc (USA) Many herpesviruses N/A Very Good
S2242 Hoechst (Germany) Many herpesviruses N/A Good
Arylsulfone derivatives Rega Institute (Belgium) betaherpesviruses N/A Good
Nexavir (formerly Kutapressin) Nexco Pharma (USA) EBV, HHV-6, CMV (generally prescribed for ME/CFS) N/A Good
AZT-lipid-PFA Tumingen University Clinic  (Germany) broad antiviral (enteroviruses, herpesviruses) 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 three compounds have shown superior antiviral efficacy, and are currently either FDA approved for clinical use or in advanced stages of clinical development:

CMX001
CMX001 is an antiviral drug developed by Chimerix, Inc. 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 underivatized CDV), allowing for heightened effectiveness at sub-cytotoxic concentrations.  CMX001 is entering Phase III clinical trials as a broad-acting anti-DNA virus agent in transplant patients, and is already being utilized via compassionate use among immunocompromised patients suffering from severe adenovirus infections.

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 has been recently demonstrated as an effective treatment for HHV-6B myocarditis in a pediatric patient.

VALOMACICLOVIR
Valomaciclovir is an anti-varicella zoster virus (VZV, HHV-3) drug initially developed by Epiphany Biosciences, Inc, and has also shown remarkable efficacy against HHV-6 in vitro.  This compound is currently in Phase III clinical trials for the treatment of shingles (caused by VZV) and in Phase II trials for the treatment of infectious mononucleosis caused by Epstein-Barr virus (EBV).

 

NON-DRUG “IMMUNOTHERAPY” TREATMENT FOR HHV-6
A novel immunotherapy has been recently developed to limit the effects of multiple viruses known to cause complications in transplant patients.  Known as “adoptive T-cell immunotherapy,” this approach offers advantages over conventional antiviral treatment strategies since there is no risk for drug toxicity and the immunotherapy can be used in patients infected with strains that are resistant to commonly used antivirals. This approach has already been utilized to limit the effects of adenovirus, CMV, and EBV in the clinical setting, and clinical investigation into the effectiveness of this strategy for the specific treatment of HHV-6 is now underway.

 

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.

Last updated: July 2013

The HHV-6 Foundation would like to thank Dr. Lieve Naesens and Dr. Jose Montoya for their assistance in the preparation of this summary.

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