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More effective cytomegalovirus prophylactic therapies needed for high-risk HSCT recipients
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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 stem cell transplantation, or HSCT, has fallen to 8% to 10% in the past decade. Yet, while the incidence of cytomegalovirus disease in HSCT recipients has improved, the indirect effects of cytomegalovirus still cause significant morbidity and mortality, and virus reactivation remains a risk factor for poor posttransplant outcomes.
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, CMV can reactivate, lead to active CMV disease when untreated, and to other opportunistic infections.
Immunological deficiency brought about by the widespread use of immunosuppressants 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 HSCT (allo-HSCT).
Indirect effects of antiviral CMV therapy
The standard treatment of CMV infection or disease has typically been IV ganciclovir or its oral prodrug, valganciclovir hydrochloride, or, alternatively, IV foscarnet sodium or cidofovir. Most transplant centers have adopted pre-emptive antiviral therapy as the strategy of choice for HSCT recipients.
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-HSCT recipients. Ganciclovir-related neutropenia — an independent negative risk factor for OS, EFS and transplant-related mortality — occurs in at least 20% to 30% of cases.
The use of 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-HSCT outcomes, including:
Need for novel CMV prophylactic therapies
Although 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 United States, 83% of people aged 60 to 69 years are CMV seropositive. Patients aged 60 years and older received 8% of all HSCTs in 2002 to 2011, a figure that jumped to 22% in 2007 to 2013. As baby boomers age, many more allogeneic transplant recipients 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-HSCT. Of these agents, letermovir was the only one to 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.
CMV disease and the indirect effects resulting from CMV replication through reactivation or new infection can be especially life-threatening for recipients of allo-HSCT. 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 United States who receive these life-saving transplants each year.
References:
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Merck. Merck announces pivotal phase 3 study of letermovir, an investigational antiviral medicine for prevention of cytomegalovirus (CMV) infection in high-risk bone marrow transplant patients, met primary endpoint. www.mercknewsroom.com/news-release/corporate-news/merck-announces-pivotal-phase-3-study-letermovir-investigational-antivir. Accessed on Jan. 17, 2017.
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For more information:
Roy F. Chemaly, MD, MPH, FIDSA, FACP, is 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. He can be reached at 1515 Holcombe Blvd., Unit 1460, Houston, TX 77030.
Disclosure: Chemaly reports research grants from Chimerix, Merck and Novartis. He also reports honoraria from and advisory board roles with Astellas, Chimerix, Merck, Novartis and Oxford Immunotec.