Suzanne Luck

Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial

Summary Background Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise. Methods We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260. Findings 67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12 537 (95% CI 6593–23 840) versus 86 (63–118) in recipients of placebo recipients; p<0·0001) and seropositive (118 395; 64 503–217 272) versus 24 682 (17 909–34 017); p<0·0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0·0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0·0480) and number of days of ganciclovir treatment (p=0·0287) were reduced in vaccine recipients. Interpretation Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients. Funding National Institute of Allergy and Infectious Diseases, Grant R01AI051355 and Wellcome Trust, Grant 078332. Sponsor: University College London (UCL).

Syphilis is on the increase: the implications for child health

Regardless of origins, syphilis has affected Europeans over many centuries. The first well-documented outbreak occurred in Naples in 1494, rapidly swept throughout Europe and was associated with a myriad of presenting signs and symptoms and a high mortality rate.1 The condition was once a leading cause of dementia and in the pre-antibiotic era caused one out of five of all admissions to psychiatric institutions in the USA.2 In 1943 Mahoney and co-workers first treated cases of syphilis with penicillin. This drug has remained the mainstay of treatment since that time.3 Horizontal transmission among adolescents and adults is primarily sexual, although anecdotal reports cite kissing, contact with infected secretions and blood transfusion as potential sources of acquisition and transmission.4 Transmission to the fetus is usually via the placenta, but may occur during delivery in the presence of maternal genital lesions. The risk of vertical transmission of syphilis from an infected untreated mother decreases as maternal disease progresses, ranging from 70–100% for primary syphilis and 40% for early latent syphilis to 10% for late latent disease (early and late latent syphilis occurring less than or more than 1 year after initial infection in adults, respectively).3 5 Although unusual, transmission to newborns from mothers with tertiary syphilis has also been reported.6 Thus, the longer the interval between infection and pregnancy, the more benign is the outcome in the infant (Kassowitz’s law).6 Syphilis is common in the developing world with localised prevalence in pregnant women varying widely from 2.5% in Burkina Faso to 17.4% in Cameroon.7 However, such data may be skewed by high numbers of false-positive assays. Data on sexually transmitted infections have been collected in the UK since 1917; such infections are currently reported by genitourinary medicine (GUM) clinics to the Health Protection Agency …

Evidence based management guidelines for the detection and treatment of congenital CMV

CMV is the most common congenital infection in newborns worldwide. Congenital CMV causes sensorineural hearing loss in a significant proportion of infected newborns, while the majority of newborns are asymptomatic. In the last three years there have been significant advances in the diagnosis and treatment of congenital CMV. We have developed practical evidence based guidelines for the management of congenital CMV.

Use of stored dried blood spots for retrospective diagnosis of congenital CMV

The diagnosis of congenital cytomegalovirus infection cannot be made with certainty in children presenting after the perinatal period, unless stored early samples are available for diagnostic testing. This has led to uncertainty in confirming the overall contribution of CMV to hearing loss and neurodevelopmental impairment. The use of dried blood spots (DBSs) to retrospectively diagnose infection in children with compatible symptoms may be helpful diagnostically although there are ongoing uncertainties regarding the stability of viral DNA in cards, the risk of contamination between cards, and sensitivity and specificity in a clinical setting. This report aims to address these areas and evaluate the use of DBS testing in our hands in the United Kingdom to date. Results from testing artificially prepared cards and cards from three populations of children suggest a high specificity for congenital CMV infection and a good sensitivity for cases where sensorineural hearing loss is caused by congenital CMV. J. Med. Virol. 81:1394–1398, 2009.

Postnatal cytomegalovirus: innocent bystander or hidden problem?

Cytomegalovirus (CMV) is a common pathogen, associated with mild illness in most immunocompetent people. Historically, research on CMV infection in the relatively immunocompromised premature and small-for-gestational age neonatal population has been neglected. Recent studies have not only defined factors important in the transmission of CMV, but also led to the suggestion of serious morbidity related to postnatal acquisition. The burden of postnatal CMV disease and the risk–benefit of screening and prevention strategies are all still unclear.

Antiviral Therapy of CMV Disease in Children

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality in infants and children. The main burden of disease occurs in congenital infection, postnatal infection in premature infants and in older immunocompromised children (now predominantly following transplantation) in developed countries. In lower income countries, CMV is a major co-pathogen in human immunodeficiency virus [HIV]-infected infants. Antiviral treatment options remain very limited. The guanosine analogue ganciclovir (GCV) was first used in children over 20 years ago, but the optimal dose, duration and route of administration remain poorly evidence based. In particular there are very limited data in premature infants and older children. Direct comparison studies between the intravenous ganciclovir and the oral valyl-ester valganciclovir (VGCV) have not been performed. CMV disease is important, but not very common and there remains a need to identify useful surrogate markers of successful antiviral therapy to facilitate clinical trials. Cidofovir and foscarnet have very significant toxicity. No other anti-CMV agent has successfully completed phase III studies. There remain few other antiviral agents effective against CMV on the horizon. This chapter reviews the current clinical spectrum of CMV disease in childhood and the evidence base for both GCV and VGCV use in clinical practice. It also discusses the antiviral studies currently being performed and those that need to be performed.

First estimates of the potential cost and cost saving of protecting childhood hearing from damage caused by congenital CMV infection

Background Congenital cytomegalovirus (cCMV) is an important cause of childhood deafness, which is modifiable if diagnosed within the first month of life. Targeted screening of infants who do not pass their newborn hearing screening tests in England is a feasible approach to identify and treat cases to improve hearing outcome. Aims To conduct a cost analysis of targeted screening and subsequent treatment for cCMV-related sensorineural hearing loss (SNHL) in an, otherwise, asymptomatic infant, from the perspective of the UK National Health Service (NHS). Methods Using data from the newborn hearing screening programme (NHSP) in England and a recent study of targeted screening for cCMV using salivary swabs within the NHSP, we estimate the cost (in UK pounds (£)) to the NHS. The cost of screening (time, swabs and PCR), assessing, treating and following up cases is calculated. The cost per case of preventing hearing deterioration secondary to cCMV with targeted screening is calculated. Results The cost of identifying, assessing and treating a case of cCMV-related SNHL through targeted cCMV screening is estimated to be £6683. The cost of improving hearing outcome for an infant with cCMV-related SNHL through targeted screening and treatment is estimated at £14 202. Conclusions The costs of targeted screening for cCMV using salivary swabs integrated within NHSP resulted in an estimate of cost per case that compares favourably with other screening programmes. This could be used in future studies to estimate the full economic value in terms of incremental costs and incremental health benefits.

Feasibility and acceptability of targeted screening for congenital CMV-related hearing loss

Background Congenital cytomegalovirus (cCMV) is the most common non-genetic cause of sensorineural hearing loss (SNHL) in children. Ganciclovir has been shown to prevent the continued deterioration in hearing of children with symptomatic cCMV, but some children with cCMV-related SNHL are unidentified in the neonatal treatment period. Neonatal cCMV screening provides an opportunity to identify infants with cCMV-related SNHL who might benefit from early treatment. Objectives To assess the feasibility (ability to take samples before 3 weeks of age and clinical assessment by 30 days of age) and acceptability (maternal anxiety) of targeted CMV testing of infants who are ‘referred’ for further audiological testing after routine newborn hearing screening programme (NHSP). Methods Parents of infants who have ‘no clear responses’ on routine NHSP before 22 days of life in London and North East England were approached. Salivary and urine samples were tested by CMV PCR. At recruitment and 3 months, the short form Spielberger State-Trait Anxiety Inventory measured maternal anxiety. Results 411 infants were recruited. 99% (407/411) returned a sample; 98% (404/411) successfully yielded a CMV result, 6 had cCMV, all diagnosed on salivary samples taken <22 days of age (1.5%; 95% CI 0.6% to 3.2%). Only 50% returned urine samples compared with 99% returning salivary samples (p<0.001). Using saliva swabs 98% were successfully screened for CMV within 3 weeks. All positive screening CMV results were known by day 23, and 5/6 infants with cCMV were assessed within 31 days. Anxiety was not increased in mothers of infants screened for cCMV. Conclusions Targeted salivary screening for cCMV within the NHSP is feasible, acceptable and detects infants with cCMV-related SNHL who could benefit from early treatment.

Ganciclovir treatment in children: evidence of subtherapeutic levels

Ganciclovir (GCV) is used to treat babies and older children with cytomegalovirus-related disease. Treatment courses are generally derived from adult studies and there are few data relating to the pharmacokinetics of GCV in children. In adults, low trough GCV levels have been associated with treatment failure and virological resistance. Data regarding suitable drug levels for use in therapeutic drug monitoring (TDM) in the paediatric age group do not currently exist. In this study, anonymised data for all GCV levels sent to the UK Antibiotic Reference Laboratory from 1 November 1999 to 31 March 2007 were reviewed and analysed by age group. In total, 339 specimens were received from 129 patients; 192 specimens were from patients aged <18 years. There were significantly more trough GCV levels <0.5 mg/L in those aged <6 months and 6-12 months compared with adults (64.8% and 53.9%, respectively, vs. 15.9%; P<0.001). Those aged 5-18 years also had significantly more trough samples with levels <0.5 mg/L (80.0% vs. 15.9%; P<0.001). There was a significant difference between median peak GCV levels in those aged <6 months and adults (4.8 mg/L vs. 5.7 mg/L, respectively; P=0.047). In conclusion, GCV levels associated with treatment failure and considered subtherapeutic in adult patients were observed more often in specimens from paediatric patients. These lower levels may have implications for dosing in the paediatric age group, particularly during periods of rapid change in renal function such as the neonatal period. Clinicians should be aware of the relatively low drug exposure noted in this study and consider TDM and increasing drug dose where virological response is poor.

Advances in the antiviral therapy of herpes virus infection in children

Herpes viruses are ubiquitous, and primary infection with many of these viruses is common during childhood. In general, children tolerate primary infection well, with only mild symptoms, but in the immunocompromised, including the newborn, infection can be associated with serious morbidity and mortality. Drug treatment for many of the herpes infections is available but is often associated with serious side effects. In the pediatric age group, treatment is further hindered by a lack of information on suitable dosing regimes, unavailability of oral solutions and a lack of clinical trials specifically investigating response to treatment in this group of patients. This article will review current evidence regarding the pharmacokinetics and dosing of the most commonly used antiherpetic agents and will look specifically at the treatment of the more common herpes virus infections in children.