First therapeutic use of Artesunate in treatment of human herpesvirus 6B myocarditis in a child

Hakacova, Nina; Klingel, Karin; Kandolf, Reinhard; Engdahl, Elin; Fogdell‐Hahn, Anna; Higgins, Thomas F.

doi:10.1016/j.jcv.2013.02.005

Cited by 42 publications

(31 citation statements)

References 25 publications

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“…It has been proven to inhibit the replication of several human herpesviruses in vitro, in particular HCMV and HHV-6, and has been given to treat HCMV infections in vivo as a compassionate use. Its mechanism of antiviral activity likely involves the modulation of cellular activation pathways involving Sp1 and NF-B (212,213). Valomaciclovir, a drug developed initially against varicella-zoster virus, has also shown significant activity against HHV-6 in vitro (214)(215)(216).…”

Section: Antiviral Agentsmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.

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Section: Antiviral Agentsmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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“…83 A case report showed artesunate was effective and safe for treating HHV-6B myocarditis. 84 Clinical trials will be required to assess the potential values of these drugs in the treatment of HHV-6-related diseases.…”

Section: Hhv-6 Encephalitis After Allo-hct M Ogata Et Almentioning

confidence: 99%

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

Ogata

Fukuda²,

Teshima

2015

Bone Marrow Transplant

107

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Human herpesvirus-6 (HHV-6) encephalitis following allogeneic hematopoietic cell transplantation is a serious and often fatal complication accompanying reactivation of HHV-6B. Incidence varies among studies, but is reportedly 0-11.6% after bone marrow or PBSC transplantation and 4.9-21.4% after umbilical cord blood transplantation, typically around 2-6 weeks post transplant. Symptoms are characterized by memory loss, loss of consciousness and seizures. Magnetic resonance imaging (MRI) typically shows bilateral signal abnormalities in the limbic system. This complication is considered to represent acute encephalitis caused by direct virally induced damage to the central nervous system, but our understanding of the etiologies and pathogenesis is still limited. The mortality rate attributable to this pathology remains high, and survivors are often left with serious sequelae such as impaired memory and epilepsy. Despite the poor prognosis, no validated treatments or preventative measures have been established. Establishment of preventative strategies represents an important challenge. This article reviews the current knowledge of the clinical features, incidence, pathogenesis and treatment of HHV-6 encephalitis, and discusses issues needing clarification in the future to overcome this serious complication.

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“…In 2008, a patient with recurrent multiresistant CMV infection was successfully treated with artesunate (19), and since then 7 more transplant patients with CMV infections were treated with varying success (20,21). Recently, a patient with multidrug-resistant herpes simplex virus 2 (HSV-2) infection (22) and a child with human herpesvirus 6B (HHV-6B) myocarditis (23) were successfully treated with artesunate. In addition, antiviral activity in vitro has also been found against other herpesviruses, including herpes simplex virus 1 (17), Epstein-Barr virus (24), and human herpesvirus 6A (25), and also to some extent against nonherpesviruses, such as hepatitis B virus (26), hepatitis C virus (27), HIV-1 (17), and bovine viral diarrhea virus (28).…”

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confidence: 99%

Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

Sharma

Marschall

Henriksen

et al. 2014

Antimicrob Agents Chemother

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dPolyomavirus BK (BKV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) in renal and bone marrow transplant patients, respectively. Antiviral drugs with targeted activity against BKV are lacking. Since the antimalarial drug artesunate was recently demonstrated to have antiviral activity, the possible effects of artesunate on BKV replication in human primary renal proximal tubular epithelial cells (RPTECs), the host cells in PyVAN, were explored. At 2 h postinfection (hpi), RPTECs were treated with artesunate at concentrations ranging from 0.3 to 80 M. After one viral replication cycle (approximately 72 hpi), the loads of extracellular BKV DNA, reflecting viral progeny production, were reduced in a concentrationdependent manner. Artesunate at 10 M reduced the extracellular BKV load by 65%; early large T antigen mRNA and protein expression by 30% and 75%, respectively; DNA replication by 73%; and late VP1 mRNA and protein expression by 47% and 64%, respectively. Importantly, the proliferation of RPTECs was also inhibited in a concentration-dependent manner. At 72 hpi, artesunate at 10 M reduced cellular DNA replication by 68% and total metabolic activity by 47%. Cell impedance and lactate dehydrogenase measurements indicated a cytostatic but not a cytotoxic mechanism. Flow cytometry and 5-ethynyl-2=-deoxyuridine incorporation revealed a decreased number of cells in S phase and suggested cell cycle arrest in G 0 or G 2 phase. Both the antiproliferative and antiviral effects of artesunate at 10 M were reversible. Thus, artesunate inhibits BKV replication in RPTECs in a concentration-dependent manner by inhibiting BKV gene expression and genome replication. The antiviral mechanism appears to be closely connected to cytostatic effects on the host cell, underscoring the dependence of BKV on host cell proliferative functions.

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First therapeutic use of Artesunate in treatment of human herpesvirus 6B myocarditis in a child

Cited by 42 publications

References 25 publications

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

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