Artesunate in Preemptive Treatment of Human Cytomegalovirus (CMV) in Stem Cell Transplant Recipients
Condition: Cytomegalovirus Infections
MeSH terms: Cytomegalovirus Infections
Study type: Interventional
Phase: Phase 3

Summary: 
      Human cytomegalovirus (HCMV) has remained a major cause of morbidity and mortality following
      allogeneic bone marrow or peripheral blood stem cell transplantation (SCT). The most reliable
      virological predictive marker for disease development is the presence of HCMV viremia. It has
      been further recognized that viral load, and viral load kinetics are important determinants
      of pathogenesis. Prior to the preventive use of antiviral agents, CMV disease occurred in
      15-45% of at-risk patients and carried a high mortality rate. In the last decade, major
      advances in the prevention of CMV disease have occurred with the application of pp65
      antigenemia and qualitative/quantitative polymerase chain reaction (PCR) assays for the rapid
      and sensitive diagnosis of HCMV infection, combined with preemptive antiviral treatment
      targeted to patients with viremia. The prevalence of early CMV disease has declined to 3% to
      6% with intense antiviral drug use. All antiviral drugs currently used for the treatment of
      systemic HCMV infection, including ganciclovir, foscarnet, and cidofovir, target the HCMV DNA
      polymerase. Ganciclovir is the most widely used drug for preemptive treatment. However,
      ganciclovir treatment is often complicated by bone marrow toxicity with the occasional
      development of potentially life-threatening thrombocytopenia, granulocytopenia, and graft
      failure, associated with secondary bacterial and fungal infection. Another limitation of
      preemptive ganciclovir therapy is the requirement for intravenous administration. The
      currently available oral valganciclovir is not yet approved for preemptive therapy in SCT
      recipients, and is associated with high treatment cost. Additionally, prolonged or repeated
      ganciclovir treatment may lead to the development of drug resistance. The use of foscarnet
      and cidofovir is limited by considerable nephrotoxicity, low oral bioavailability, and high
      cost. Thus, there is an increasing need for new effective non-toxic, low-cost anti-HCMV drugs
      with high oral bioavailability.

      Recently, the anti-malaria drug artesunate, which is widely used in the treatment of severe
      malaria, has been shown to be a highly effective inhibitor of HCMV in vitro. Artesunate
      exhibited similar antiviral activity (same micromolar range) to that of ganciclovir, while
      demonstrating no cytotoxicity. Importantly, its antiviral activity has been further
      demonstrated in vivo in a rat CMV model. No significant side effects were demonstrated in a
      number of pre-clinical and clinical studies, and artemisinin and its derivatives have been
      shown to be well-tolerated and safe in adults and children. Several million people have taken
      artemisinins to date, with no significant adverse or treatment-limiting effects being
      reported. Although neurotoxicity has been reported with supraphysiological doses in animals,
      it has not been documented in humans. Meta-analyses of malaria patients treated with
      artemisinins demonstrated that this drug class is safe. In rare cases, however, slight
      changes to haematology values have been seen, including a reduction in the number of
      reticulocytes as well as a slight increase in transaminase levels. These signs, however, do
      not generally give rise to any noticeable clinical manifestations. In rare cases, a slight
      but transient reduction in sinus heart rate has been observed. Abdominal cramps and mild
      diarrhoea have been reported at elevated doses.

      Thus, one might expect a similarly high degree of safety for the potential use of artesunate
      as an antiviral drug for HCMV infection. Thus, oral therapy with artesunate could be a
      beneficial option to the current therapies for the preemptive treatment of HCMV disease in
      SCT recipients.
    


Intervention name(s): Artesunate
Intervention type(s): Drug
Intervention description(s): PO Artesunate
Intervention MeSH terms: Artesunate
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: bone marrow transplantation; CMV disease