Antiviral therapy for cytomegalovirus infections in pediatric patients

doi:10.1053/spid.2002.29754

Seminars in Pediatric Infectious Diseases

Volume 13, Issue 1, January 2002, Pages 22-30

https://doi.org/10.1053/spid.2002.29754 Get rights and content

Abstract

Appreciation of the spectrum of illness caused by cytomegalovirus (CMV) infections has increased markedly during the past 2 decades. The number of immunosuppressed patients also has increased during the same time period, reflecting the central tenet that CMV disease is most severe in this patient population. Fortunately, antiviral therapies with activity against CMV also have been identified during this same time course, and they include ganciclovir, foscarnet, and cidofovir. Although all 3 of these therapies can have significant toxicities associated with them, nonetheless they are employed with relative frequency to treat potentially life-threatening CMV disease. Ganciclovir is the first-line compound used, followed by foscarnet and cidofovir. This article summarizes those CMV infections that require antiviral therapy and outlines therapeutic options for each. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

CMV

Human CMV is a member of the β-herpesviruses, along with human herpesvirus-6 and human herpesvirus-7. As with all human herpesviruses, CMV DNA is contained within a nucleocapsid of 162 hexagonal capsomeres. The nucleocapsid is surrounded by an ill-defined tegument, which in turn is surrounded by a loosely applied lipid envelope. Based on restriction enzyme analysis of viral DNA, multiple genetic variants, or strains, of CMV exist. Persons infected with 1 strain of CMV show cross-reactive

Ganciclovir

Ganciclovir is a nucleoside analogue that, compared with acyclovir, has an extra hydroxymethyl group on the acyclic side chain.²⁴ Its greatest in vitro activity is against CMV, although it is active also against HSV-1, HSV-2, and VZV. As with many other nucleoside analogues used to treat herpesvirus infections, the first step in ganciclovir phosphorylation in infected cells is performed by a virus-encoded enzyme, converting ganciclovir to its monophosphate derivative. Di-phosphorylation and

Disease syndromes, diagnosis, and indications for treatment

Primary CMV infection in the immunocompetent child or adult almost always is asymptomatic, except for occasional cases of infectious mononucleosis. These latter patients present with a fever spiking over 38°C and with few localizing symptoms. Pharyngitis, lymphadenopathy, and splenomegaly are less common occurrences than in Epstein-Barr virus mononucleosis. Laboratory tests show biochemical hepatitis, with moderately raised transaminases, lymphocytosis with atypical mononuclear cells, and a

Disease syndromes, diagnosis, and indications for treatment

In the immunocompromised host, active CMV infections cause a wide spectrum of disease, ranging from asymptomatic to life-threatening. The unifying feature of CMV disease in the immunocompromised transplant recipient is the presence of fever. It typically follows a spiking pattern, with temperatures in the range of 38°C to 40°C, followed by precipitous declines below 37°C. During the fever, the patient complains of malaise and lethargy and may develop myalgia or arthralgia. This systemic phase

Ganciclovir

The usual therapeutic and prophylactic dose of ganciclovir is 10 mg/kg/d, given by intravenous infusion twice a day for 2 to 3 weeks. For continued suppressive therapy to prevent relapse of infection (eg, in patients with AIDS) or long-term prophylaxis, either of the following may be used: (1) 5 mg/kg as a single daily dose each day of the week or (2) 6 mg/kg administered 5 days a week. Prophylactic oral ganciclovir (1,000 mg 3 times daily) recently was shown to significantly reduce the risk of

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For example, HSV-2 infection can involve the central nervous system where it induces the abrupt onset of fever and focal neurological symptoms. In addition, vertical transmission of virus from mother to infant and infections in immune compromised individuals can lead to viral encephalitis and/or dissemination of virus throughout the body [6]. In the absence of treatment with nucleoside analogs, the mortality rate for these infants is 50% [6].
An estimated 1 out of every 5 Americans is infected with herpes simplex virus type 2 (HSV-2). Efforts in developing a potent vaccine for HSV-2 have shown limited success. Here we describe a heterologous vaccination strategy for HSV-2 based on an intramuscular DNA prime followed by a liposome-encapsulated antigen boost delivered intranasally. Both portions of the vaccine express the immunogenic HSV-2 glycoprotein D. In female Balb/c mice, this heterologous immunisation regimen stimulated high titers of serum neutralising antibodies, a DNA priming dose dependent T helper type response, enhanced mucosal immune responses and potent protective immunity at the portal of entry for the virus: the vaginal cavity. A clear synergistic effect on immune responses and protection from infection was seen using this heterologous immunisation approach. Suboptimal DNA prime (0.5 μg) followed by the liposome boost resulted in an 80% survival rate when mice were infected 2 weeks after immunisation. A higher dose of DNA priming (5 μg) followed by the liposome boost resulted in sterilising immunity in 80% of mice. The vaccine induced durable protection in mice, demonstrated by a 60% survival rate when lethal infections were performed 20 weeks after the immunisation primed with 0.5 μg of DNA vaccine.
Newborn screening for congenital cytomegalovirus: Options for hospital-based and public health programs
2009, Journal of Clinical Virology
Citation Excerpt :
The two main potential benefits of screening for congenital CMV are (1) treatment to prevent the onset or progression of hearing loss and (2) identification of children at risk for late-onset or progressive hearing loss or other CMV-associated impairments or disabilities. At present, antiviral treatments for congenital CMV infection have modest efficacy and pose serious risks of toxicity; thus, they should only be considered for infants with severe, symptomatic infections.21 Consequently, the rationale for CMV screening at present is early detection and intervention among children at risk for CMV-associated hearing loss not detectable at birth.
Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL) and developmental disability in children. Early identification of infected children through screening could allow for early intervention and improvement in functional outcomes among the subset who develop sequelae.
To outline potential options and strategies for screening newborns for congenital CMV infection and to discuss barriers to screening and data needs to inform future policy decisions.
Commentary based on the literature and expert opinion on newborn dried blood spot screening, newborn hearing screening/Early Hearing Detection and Intervention (EHDI) programs, and congenital CMV.
Although no population-based screening for congenital CMV is underway, pilot newborn screening studies using a variety of assays with urine or dried blood spot specimens are underway. Challenges to screening are both practical—uncertain sensitivity of blood spot assays suitable for large-scale screening and lack of infrastructure for collection of urine specimens; and evidentiary—the need to demonstrate improved outcomes and value of screening to offset the expense and potential adverse psychosocial consequences for children and families whose children require periodic monitoring but never develop sequelae.
Screening for congenital CMV infection is a potentially important intervention that merits additional research, including the logistical feasibility of different screening options and psychosocial consequences for families.
CYTOMEGALOVIRUS
2009, Feigin and Cherry's Textbook of Pediatric Infectious Diseases, Sixth Edition
Antiviral therapy of congenital cytomegalovirus infection
2005, Seminars in Pediatric Infectious Diseases
Congenital infection caused by human cytomegalovirus (CMV) is a common occurrence, but its significance is underappreciated. In the developed world, congenital CMV infection confers a tremendous medical and economic burden on society. In recent years, appreciation of the scope of disability produced by such infections in newborns, which includes neurodevelopmental sequelae and sensorineural hearing loss (SNHL), has increased. Although much of the injury produced by infection in utero likely is irreversible, antiviral therapy of newborns with CMV infection is an option available to clinicians. Currently three antivirals are licensed for treatment of CMV: ganciclovir (and its prodrug, valganciclovir), foscarnet, and cidofovir. Novel antiviral therapies, which employ mechanisms of action that differ from these agents, also are in development. Experience with these agents in the setting of congenital and perinatal CMV infection is limited, but encouraging data come from a controlled clinical trial indicating that ganciclovir therapy may be of value in limiting the neurodevelopmental injury, particularly SNHL, caused by congenital infection. Newborn screening programs for CMV infection need to be developed and implemented. Infants with congenital CMV infection, once identified, could then be considered as candidates for antiviral therapy, and careful neurodevelopmental and hearing screening follow-up care plans could be established. CMV vaccines, once available, may ultimately be the best control strategy for this important public health problem.
The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs
2005, Antiviral Research
New antiviral drugs are needed for the treatment of cytomegalovirus (CMV) infections, particularly in immunocompromised patients. These studies evaluated the in vitro and in vivo activity of the non-nucleosidic CMV inhibitor, BAY 38-4766, against guinea pig cytomegalovirus (GPCMV). Plaque reduction assays indicated that BAY 38-4766 was active against GPCMV, with an IC₅₀ of 0.5 μM. Yield reduction assays demonstrated an ED₉₀ and ED₉₉ of 0.4 and 0.6 μM, respectively, of BAY 38-4766 against GPCMV. Guinea pigs tolerated oral administration of 50 mg/kg/day of BAY 38-4766 without evidence of biochemical or hematologic toxicity. Plasma concentrations of BAY 38-4766 were high following oral dosing, with a mean peak level at 1-h post-dose of 26.7 mg/ml (n = 6; range, 17.8–35.4). Treatment with BAY 38-4766 reduced both viremia and DNAemia, as determined by a real-time PCR assay, following GPCMV infection of cyclophosphamide-immunosuppressed strain 2 guinea pigs (p < 0.05, Mann–Whitney test). BAY 38-4766 also reduced mortality following lethal GPCMV challenge in immunosuppressed Hartley guinea pigs, from 83% (20/24) in placebo-treated guinea pigs, to 17% (4/24) in BAY 38-4766-treated animals (p < 0.0001, Fisher's exact test). Mortality differences were accompanied by reduction in DNAemia in Hartley guinea pigs. Based upon its favorable safety, pharmacokinetic, and therapeutic profiles, BAY 38-4766 warrants further investigation in the GPCMV model.
Treatment of interstitial lung disease in children
2004, Paediatric Respiratory Reviews
The treatment of interstitial lung disease in children depends on the nature of the underlying pathology. In approximately 50% of cases a specific aetiology can be found such as: chronic viral infection, an auto-immune process, sarcoidosis or alveolar proteinosis. In the remainder, the process is idiopathic and the pathological findings are based on the descriptive morphological features seen in the diagnostic lung biopsy. If a specific cause is found then targeted treatment with antivirals, steroids or other immunosuppressive agents is available. Alveolar proteinosis can be treated by bronchial lavage and GM-CSF. Idiopathic cases are treated primarily with intravenous pulsed methylprednisolone or oral prednisolone backed up hydroxychloroquine. Other immunosuppressive agents such as azathioprine, methotrexate or ciclosporin have been used successfully in individual patients.
The prognosis is very variable and includes no response to any therapy, partial response with chronic long term morbidity, to virtually complete recovery. The overall mortality rate is 15%.
There are no controlled therapeutic trials available because of the rarity of these conditions in childhood. Unlike in adult practice, no correlation has as yet been demonstrated between the initial pattern of chest x-ray change or the degree of pathological change on the lung biopsy and the clinical outcome.
The recurrence rate within families is 1 in 8.

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^*: Supported under contract with the Virology Branch, Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases (NIAID), NO1-AI-15113 and NOI-AI-62554, and by grants from the General Clinical Research Center Program (RR-032) and the State of Alabama.

^**: Address correspondence to David W. Kimberlin, MD, Assistant Professor of Pediatrics, The University of Alabama at Birmingham, Division of Pediatric Infectious Diseases, 1600 Seventh Ave S, Suite 616, Birmingham, AL 35233; e-mail: [email protected]

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ArticlesAntiviral therapy for cytomegalovirus infections in pediatric patients*,**

Abstract

Section snippets

CMV

Ganciclovir

Disease syndromes, diagnosis, and indications for treatment

Disease syndromes, diagnosis, and indications for treatment

Ganciclovir

Virology

J Pediatr

J Pediatr

J Biol Chem

Am J Kidney Dis

Lancet

J Clin Virol

Antiviral Res

J Heart Lung Transplant

J Clin Virol

Ophthalmology

Cytomegalovirus

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J Infect Dis

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N Engl J Med

Cytomegalovirus infection in day care center

N Engl J Med

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Pediatr Res

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J Infect Dis

The molecular epidemiology of cytomegalovirus transmission among children attending a day care center

J Infect Dis

Increased rate of cytomegalovirus infection among parents of children attending day care centers

N Engl J Med

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Pediatr Infect Dis

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N Engl J Med

Virus-specific antibody responses in mothers and their newborn infants with asymptomatic congenital cytomegalovirus infections

J Infect Dis

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Am J Dis Child

Outcome of symptomatic congenital cytomegalovirus infection: Results of long-term longitudinal follow-up

Pediatrics

Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection

J Pediatr

Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus

J Am Acad Audiol

Molecular epidemiology of cytomegalovirus infections associated with bone marrow transplantation

Ann Intern Med

A prospective study of primary cytomegalovirus infection during pregnancy: Final report

Br J Obstet Gynaecol

Ganciclovir: An update of its therapeutic use in cytomegalovirus infection

Drugs

A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells

Nature

Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir

Nature

Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses

Antimicrob Agents Chemother

Comparative pharmacokinetics of antiviral nucleoside analogues

Clin Pharmacokinet

Molecular detection of human cytomegalovirus and determination of genotypic ganciclovir resistance in clinical specimens

Clin Infect Dis

Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections

Clin Pharmacol Ther

BW B759U for cytomegalovirus retinitis: Intraocular drug penetration

Arch Ophthalmol

Intravitreal ganciclovir concentration after intravenous administration in AIDS patients with cytomegalovirus retinitis: Implications for therapy

J Infect Dis

Human pharmacokinetics of the antiviral drug DHPG

Clin Pharmacol Ther

Human pharmacokinetics and tolerance of oral ganciclovir

Antimicrob Agents Chemother

Articles
Antiviral therapy for cytomegalovirus infections in pediatric patients*,**