Healio
Healio
Issue: February 2017
ByRoy F. Chemaly, MD, MPH, FACP, FIDSA
February 16, 2017
4 min read
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More effective CMV prophylactic therapies needed for high-risk HCT patients

Issue: February 2017
ByRoy F. Chemaly, MD, MPH, FACP, FIDSA
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Due to advances in diagnostic methods and the development of preventive or pre-emptive strategies, the incidence of cytomegalovirus disease after hematopoietic cell transplantation, or HCT, has fallen to 8% to 10% in the past decade. Yet, while the incidence of cytomegalovirus disease in HCT patients has improved, the indirect effects of cytomegalovirus still cause significant morbidity and mortality, and virus reactivation remains a risk factor for poor post-transplant outcomes.

Roy F. Chemaly

Cytomegalovirus (CMV) is a common herpes virus that infects people of all ages. In the United States, CMV infects nearly one in three children by the age of 5 years and more than half of adults aged 40 years and older. Most healthy people who acquire CMV after birth have few if any symptoms and no long-term health consequences. Once an infection occurs, however, CMV establishes lifelong latency and may reactivate intermittently. When a person’s immune system becomes suppressed or compromised due to therapeutic drugs (such as those given for transplantations) or disease such as AIDS, CMV can reactivate, lead to active CMV disease when untreated, and to other opportunistic infections (like fungal).

Immunological deficiency brought about by the widespread use of immuno-suppressants in oncology and for transplantation is a major determinant of CMV disease. In fact, CMV is the single most important infectious agent following organ transplantation and a leading cause of illness in patients who have undergone allogeneic HCT (allo-HCT).

Indirect effects of antiviral CMV therapy

The standard treatment of CMV infection or disease has typically been IV Cytovene (ganciclovir, Roche Palo) or its oral prodrug, Valcyte (valganciclovir hydrochloride, Hoffmann-La Roche), or, alternatively, IV Foscavir (foscarnet sodium, Clinigen) or Vistide (cidofovir, Gilead Sciences). Most transplant centers have adopted pre-emptive antiviral therapy as the strategy of choice for HCT patients.

Although these therapies are efficacious, they have been associated with clinically significant drug-specific toxicities, including myelosuppression (neutropenia or thrombocytopenia with ganciclovir, valganciclovir and cidofovir) and renal toxicity (with foscarnet and cidofovir), that complicate their use in allo-HCT patients. Ganciclovir-related neutropenia, which is an independent negative risk factor for overall and event-free survival and transplant-related mortality, occurs in at least 20% to 30% of cases.

The use of current anti-CMV drugs as prophylaxis or as a pre-emptive treatment also does not prevent most of the indirect effects of CMV that can lead to poor allo-HCT patient outcomes, including:

  • increased incidence of acute and extensive chronic graft-versus-host disease;
  • increased risk and mortality due to bacterial and fungal infections; and
  • an increase in transplant-related mortality and a decrease in overall survival.

An intensifying need for novel CMV prophylactic therapies

While available anti-CMV drugs have decreased the incidence of CMV infections, their use for prophylaxis has not been associated with improved outcomes. Prophylactic antiviral compounds that could effectively control viral replication and restrict some pathologic processes of CMV diseases could potentially lessen the complications associated with CMV infection and possibly improve outcomes for CMV–seropositive recipients.

Demographic and transplant trends heighten the need for new anti-CMV agents. In the U.S., 83% of people aged 60 to 69 years are CMV seropositive. Patients aged 60 years and older received 8% of all hematopoietic cell transplants in 2002-2011, a figure that jumped to 22% in 2007-2013. As Baby Boomers age, many more allogeneic transplant patients will be CMV seropositive.

Though no new anti-CMV compounds have been approved since 1995, three — letermovir (Merck), brincidofovir (Chimerix) and maribavir (ViroPharma) — have been studied in prophylactic clinical trials in allo-HCT. Of these agents, letermovir was the only one to successfully meet its primary efficacy endpoint in a global, multicenter phase 3 study. The primary outcome measure was the percentage of participants with clinically significant CMV infection through 24 weeks after transplant. In an earlier phase 2 study, prophylactic therapy with letermovir was shown to be efficacious, and as safe as placebo, with no apparent safety concerns, including hematologic and renal toxicity.

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CMV disease and the indirect effects resulting from CMV replication through reactivation or new infection can be especially life-threatening for recipients of allo-HCT. New antivirals with high anti-CMV potency and a good safety profile would help address an urgent unmet therapeutic need for more than 8,000 patients in the U.S. who receive these life-saving transplants each year.

  • For more information:
  • Roy F. Chemaly, MD, MPH, FIDSA, FACP, is a professor of medicine, director of the infection control section, and director of the clinical virology research program in the department of infectious diseases, infection control and employee health at The University of Texas MD Anderson Cancer Center, Houston, Texas.

Disclosure: Chemaly reports receiving research grants from Chimerix, Merck and Novartis. He also has received honoraria from and served on advisory boards for Astellas, Chimerix, Merck, Novartis and Oxford Immunotec.

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