Curr Treat Options Infect Dis. Published online Jun Author information Copyright and License information Disclaimer. Corresponding author. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author s and the source are credited.
This article has been cited by other articles in PMC. Opinion statement In treating cytomegalovirus CMV infection, it is crucial to decide whether one is treating pre-emptively or if one is treating established disease.
Keywords: cytomegalovirus, pre-emptive therapy, retinitis, encephalitis, pneumonitis, ganciclovir, valganciclovir, foscarnet, cidofovir, drug resistance, maribavir, adoptive immunotherapy, CMX Introduction Cytomegalovirus CMV infection is a common complication of immunosuppression, and is frequently seen in transplant recipients, patients with the acquired immunodeficiency syndrome AIDS , and those who have received steroids [ 1 ].
Treatment When there were no anti-viral medications effective against CMV, the only option physicians had was reduction of immunosuppression [ 2 ].
Pharmacologic treatment The standard drugs The first-line options for therapy of CMV disease, as mentioned above, are almost always i.
Oral valganciclovir The earliest large study that demonstrated non-inferiority of p. Table 1 When should CMV drug resistance be considered? Open in a separate window. Leflunomide Leflunomide is an immunosuppressive agent, approved for rheumatoid arthritis, that appears to inhibit virion assembly rather than DNA synthesis [ 69 ].
Surgery Surgery has a limited role in the management of CMV disease, but it is invaluable in severe CMV colitis with either uncontrollable hemorrhage or toxic megacolon. Other treatments The role of CMV-Ig Although several studies show the utility of CMV-Ig as a prophylactic agent in transplant recipients, very few studies describe their use for the treatment of infection or disease [ 75 ]. Emerging therapies The importance of the immune system Although drugs are important in the control of CMV infection, the immune system is even more important.
Summary Much progress has been made against CMV in transplantation. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading. Rubin RH. Infection in organ transplant recipients. Clinical approach to infection in the compromised host. New York: Plenum; Cytomegalovirus infection. Oxford textbook of medicine. Oxford: Oxford University Press; Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Boeckh M, Ljungman P. How I treat cytomegalovirus in hematopoietic cell transplant recipients.
Cytomegalovirus PP65 antigenemia monitoring as a guide for preemptive therapy: a cost effective strategy for prevention of cytomegalovirus disease in adult liver transplant recipients. Interrelationships among quantity of human cytomegalovirus HCMV DNA in blood, donor-recipient serostatus, and administration of methylprednisolone as risk factors for HCMV disease following liver transplantation.
J Infect Dis. Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy. Am J Transplant. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Why valganciclovir should not be indicated for liver recipients and high-dose acyclovir should not be removed from international cytomegalovirus guidelines.
A randomized, controlled trial comparing ganciclovir to ganciclovir plus foscarnet each at half dose for preemptive therapy of cytomegalovirus infection in transplant recipients.
N Engl J Med. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Accessed at hrs, 6 March Clinical features and outcomes of cytomegalovirus retinitis after transplantation.
Transpl Infect Dis. Cytomegalovirus-associated chorioretinitis after liver transplantation: case report and review of the literature. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Kuppermann BD, Jose I, et al. Intravitreal ganciclovir concentration after intravenous administration in AIDS patients with cytomegalovirus retinitis: implications for therapy.
Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. Evaluation of a score system for the severity and outcome of cytomegalovirus interstitial pneumonia in allogeneic bone marrow recipients.
J Infect. Activity of 9-[2-hydroxy hydroxymethyl ethoxymethyl]guanine in the treatment of cytomegalovirus pneumonia.
Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplant. Treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovir and intravenous immune globulin: experience of European Bone Marrow Transplant Group. Cytomegalovirus interstitial pneumonia in autologous bone marrow transplant recipients. Bone Marrow Transplant. Use of Cytomegalovirus intravenous immune globulin for the adjunctive treatment of cytomegalovirus in hematopoietic stem cell transplant recipients.
The Sanford guide to antimicrobial therapy Sperryville: Antimicrobial therapy, Inc; Cytomegalovirus disease. AIDS therapy. Philadelphia: Churchill Livingston Elsevier; The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients. Early diagnosis and successful treatment of acute cytomegalovirus encephalitis in a renal transplant recipient.
J Neurol. Cytomegalovirus ischemic colitis and transverse myelitis in a renal transplant recipient. Saudi J Kidney Dis Transplant. Corneal endotheliitis associated with evidence of cytomegalovirus infection. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol. Chee SP, Jap A. Cytomegalovirus anterior uveitis: outcome of treatment. Br J Ophthalmol. Cytovene-IV package insert. Ganciclovir for severe cytomegalovirus primary infection in an immunocompetent child.
Siciliano RF, et al. Cytomegalovirus colitis in immunocompetent critically ill patients. Int J Infect Dis. Cytomegalovirus myopericarditis and hepatitis in an immunocompetent adult: successful treatment with oral valganciclovir. Inter Med. Severe cytomegalovirus infection in immunocompetent patients. Cundy KC. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin Pharmacokinet. The clinical utility of whole blood versus plasma cytomegalovirus viral load assays for monitoring therapeutic response.
Valganciclovir as treatment for cytomegalovirus disease in solid organ transplant recipients. Fellay J, Aubert JD. Treatment of cytomegalovirus infection or disease in solid organ transplant recipients with valganciclovir. Efficacy of valganciclovir in the treatment of cytomegalovirus disease in kidney and pancreas transplant recipients.
The availability of antiviral therapy has provided major advances in the treatment and prevention of CMV infection and has resulted in dramatically improved outcomes for immunocompromised hosts.
At the same time, the clinical utility of most of these agents is limited by poor oral bioavailability, associated toxicities, and the potential for development of resistance with extended use. Novel therapeutic agents are needed to address these limitations.
The chemical structure is demonstrated in Figure 1. The 2-dimensional structure of letermovir. Its pre-clinical profile indicated that it was highly selective in its antiviral activity for CMV, demonstrating little activity against other human or rodent herpesviruses, and minimal activity against other human pathogenic viruses, hepadnavirus, adenovirus, retroviruses, orthomyxoviruses, and flaviviruses [ 49 ]. Letermovir has shown potent in vitro and in vivo activity against CMV [ 48 , 49 ] by acting late in the CMV replication cycle.
Its mechanism of action is illustrated in Figure 2. Site-specific cleavage by the CMV terminase complex converts concatemeric progeny DNA to unit-length genomes and the packaging of those genomes into preformed procapsids ensues. The pUL51 protein is a third member of the terminase complex that has been recently characterized in detail.
It co-localizes with pUL89 and pUL56, and is required for cleavage of concatermeric DNA, although its mechanism of action is incompletely elucidated [ 45 ]. In addition to these viral gene products, a number of other viral genes are involved in the process of cleavage and assembly [ 33 ].
Letermovir interacts with the viral pUL56 subunit [ 51 ], [ 52 ] and therefore blocks viral replication without inhibiting the synthesis of progeny CMV DNA or viral proteins. This mechanism is distinct from that of the DNA polymerase inhibitors. Specific mutations in the UL56 coding sequence have been identified that confer resistance to AIC, confirming that pUL56 is a molecular target of this agent [ 52 ].
Simplified schematic representation of mechanism of action of letermovir compared to other CMV antivirals. For more detailed overview of CMV replication see [ 57 ]. Following infection of cell, viral nucleocapsid traffics to nucleus 1 , followed by entry of linear viral DNA into nuclear compartment via nuclear pore 2. Viral genomic DNA then circularizes 3 , followed by initiating of viral DNA replication via a rolling circle mechanism 4. Panel B, mode of action of letermovir.
After rolling circle replication of multiple concatemers of genomic DNA 1 , a collection of viral proteins known as the CMV terminase complex converts concatemeric progeny DNA to unit-length genomes 2.
The major components of the terminase complex are pUL89 and pUL56 the molecular target of letermovir. Subsequently, the packaging of these unit length genomes into preformed procapsids ensues 3 prior to egress of the mature nucleocapsid through the nuclear membrane 4 , the next step in virion assembly. Inhibition of cleavage of concatermeric DNA into unit length genomes prevents completion of viral replication.
Since letermovir works at a later stage of CMV replication than DNA polymerase inhibitors, other CMV proteins are made in infected cells in the context of exposure to this antiviral. This in turn might theoretically translate to development of anti-viral immune responses to these proteins in patients treated with letermovir, compared to ganciclovir, although this is speculative and has not been evaluated in clinical studies.
The pharmacokinetic properties of AIC have been monitored in nine Phase I trials so far [ 39 , 40 ]. After a single oral dose, absorption is reported to occur rapidly with median Tmax of 1. Letermovir has been administered to over healthy subjects, either as a single dose or repeated doses for up to 14 days.
In an open-label, proof-of-concept trial Phase IIa , 27 transplanted patients with CMV viremia were enrolled and treated pre-emptively with daily doses of 80 mg letermovir for 14 days [ 48 ]. The reduction in viral CMV DNA load in kidney-transplanted patients was similar when compared with the local standard treatment at the investigational site, and no patient was noted to develop CMV disease while on therapy. It is noteworthy that in this trial, letermovir was used to successfully treat a lung transplant patient who developed multi-resistant CMV pneumonitis on Val-GCV prophylaxis described in greater detail below [ 53 ].
No tolerability or safety issues related to letermovir treatment occurred during the treatment period in either phase I or phase IIa studies.
In all trials, letermovir was generally well tolerated as no dose-dependent adverse events occurred and no effects on safety laboratory parameters, vital signs or electrocardiogram ECG parameters have been reported [ 50 ]. As noted above, phase 1 clinical trials have demonstrated that letermovir has a favorable pharmacokinetic profile allowing once daily dosing with good tolerability in more than healthy volunteers [ 50 ].
Letermovir was initiated in this patient at mg and mg every other day for 49 days. CMV viremia resolved on Day 28 with resolution of colitis, pneumonitis and retinitis. The patient had no adverse effects to the letermovir and reportedly remained CMV-relapse free for 4 months following the cessation of therapy [ 53 ].
One hundred and thirty-two HSCT recipients met entry criteria and were CMV seropositive within a year of the transplant, had no detectable CMV replication within 5 days of starting study drug, and were transplanted within 40 days of randomization.
The study participants were randomized to 60mg, mg, mg vs. The drug appeared to be safe in this reported studies. Treatment emergent adverse events considered related to the treatment or leading to discontinuation of treatment was lower in those receiving letermovir In the open-label, proof-of-concept study of letermovir [ 54 ], it was reported that co-administration of this agent with immunosuppressive drugs in patients did not result in a need for major adjustments of the co-administered immunosuppressants.
In the patient with multi-drug resistant CMV, tacrolimus levels did not require any adjustments while the patient was on letermovir therapy [ 53 ]. To date, no drug-drug interactions have been reported for letermovir. AiCuris recently announced a partnership with Merck to enter into an exclusive worldwide license agreement for future investigational studies of letermovir.
Priya S. Mark R. National Center for Biotechnology Information , U. Drugs Future. Author manuscript; available in PMC Oct Verghese and Mark R. Author information Copyright and License information Disclaimer. Verghese: ude. Schleiss: ude. Copyright notice. See other articles in PMC that cite the published article. Summary Novel therapies are urgently needed for the management of cytomegalovirus CMV disease in high-risk patients.
Background Infections with human cytomegalovirus CMV are generally asymptomatic in healthy hosts, but can cause severe disease in immune suppressed patients, including patients with advanced HIV disease, hematopoietic stem cell transplant HSCT and solid organ transplant SOT patients as well as congenitally infected patients [ 1 ]. This disrupts further chain elongation [ 55 ] Inhibition of viral encapsidation and nuclear egress of viral particles from infected cells Toxicities None reported Mild side effects include abdominal pain or discomfort, and aphthous stomatitis [ 38 ] Taste disturbance, Skin rash [ 56 ] Viral gene targets Viral pUL56 subunit Viral DNA polymerase Viral pUL97 kinase.
Open in a separate window. Mechanism of action Letermovir has shown potent in vitro and in vivo activity against CMV [ 48 , 49 ] by acting late in the CMV replication cycle. Pharmacokinetics and Metabolism The pharmacokinetic properties of AIC have been monitored in nine Phase I trials so far [ 39 , 40 ].
Amniocentesis is generally recommended when abnormalities that might be caused by CMV are seen on ultrasound. If your doctor suspects your baby has congenital CMV , it's important to test the baby within the first three weeks of birth. If your baby has CMV , your doctor likely will recommend additional tests to check the health of the baby's organs, such as the liver and kidneys.
Testing for CMV can also be important if you have a weakened immune system. Treatment generally isn't necessary for healthy children and adults. Healthy adults who develop CMV mononucleosis generally recover without medication. Newborns and people who have weakened immunity need treatment when they're experiencing symptoms of CMV infection. The type of treatment depends on the signs and symptoms and their severity.
Antiviral medications are the most common type of treatment. They can slow reproduction of the virus, but can't eliminate it. Researchers are studying new medications and vaccines to treat and prevent CMV. Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.
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