Safety considerations with current and emerging antiviral therapies for cytomegalovirus infection in transplantation

ABSTRACT

Introduction: Human cytomegalovirus (HCMV) is a major contributor of morbidity and mortality, and its management is essential for the successful outcome of solid organ and hematopoietic stem cell transplantation.

Areas covered: This review discusses the safety profiles of currently available and emerging antiviral drugs and the other strategies for HCMV prevention and treatment after transplantation.

Expert opinion: Strategies for management of HCMV rely largely on the use of antiviral agents that inhibit viral DNA polymerase (ganciclovir/valganciclovir, foscarnet, and cidofovir/brincidofovir) and viral terminase complex (letermovir), with different types and degrees of adverse effects. An investigational agent, maribavir, exerts its anti-CMV effect through UL97 inhibition, and its safety profile is under clinical evaluation. In choosing the antiviral medication to use, it is important to consider these safety profiles in addition to overall efficacy. In addition to antiviral drugs, reduction of immunosuppression is often generally needed in the management of HCMV infection, but with a potential risk of allograft rejection or graft-versus-host disease. The use of HCMV-specific or non-specific intravenous immunoglobulins remains debated, while adoptive HCMV-specific T cell therapy remains investigational, and associated with unique set of adverse effects.

Trial registration: ClinicalTrials.gov identifier: NCT03443869.

Trial registration: ClinicalTrials.gov identifier: NCT02927067.

Trial registration: ClinicalTrials.gov identifier: NCT02931539.

Trial registration: EU Clinical Trials Register identifier: 2015-004726-34.

Trial registration: EU Clinical Trials Register identifier: 2015-004725-13.

KEYWORDS:

• Ganciclovir
• letermovir
• maribavir
• foscarnet
• cidofovir
• cytomegalovirus
• transplantation

Article highlights

• HCMV is a cause of major morbidity and mortality in the transplant population

• Ganciclovir is the preferred antiviral drug for CMV management, but myelosuppression is a significant adverse toxicity

• Foscarnet and cidofovir are considered second line agents due to high toxicity rates, notably nephrotoxicity

• Letermovir is an option for HCMV prophylaxis, but low barrier to resistance and the lack of clinical trial data hinders its use for treating active HCMV infection

• Maribavir is an investigational drug that may be another option for HCMV management, but it is associated with adverse gastrointestinal side effects

• Reduction of immunosuppression should be considered, when feasible, with its benefits weighed against the risk of allostimulation and graft rejection

• IvIG and HCMV-IG use remains debatable, and their use may be associated with potential hemodynamic adverse events

• Cytotoxic T-lymphocyte infusions is an investigational strategy that may be used for the treatment of refractory/resistant HCMV infection, with the risk of potential cytokine release syndrome or GVHD

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.