Artesunate in Preemptive Treatment of Human Cytomegalovirus (CMV) in Stem Cell Transplant Recipients
Status:
Completed
Trial end date:
2010-03-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 3
Details
Lead Sponsor:
Hadassah Medical Organization
Collaborators:
Institut für Klinische und Molekulare Virologie University of Erlangen-Nürnberg Medical School