Primary infection with the varicella-zoster virus (VZV) causes chickenpox. In most healthy children, it presents as a self-limiting pruritic vesicular rash.
The virus can then enter a dormant period in the dorsal root ganglia. Reactivation of VZV manifests as herpes zoster (HZ). This can be an exceedingly painful vesicular rash distributed across a single dermatome – shingles.
Reactivation of the virus is provoked by a weakened immune surveillance system. Therefore, immunocompromised patients are at high risk and may suffer a more severe course, with delayed healing of lesions.
Currently, the treatment of cutaneous zoster is the anti-viral aciclovir. The nucleoside analogue reduces viral replication and disease progression. Immunocompromised patients require 8-hourly intravenous therapy and risks renal dysfunction. It is most often used as an inpatient treatment.
Although oral aciclovir is available, it is poorly absorbed, with only 20% bioavailability. This makes it a less favourable option, particularly in this vulnerable cohort. An efficacious oral drug provided in an outpatient setting to otherwise stable immunocompromised patients would be wonderful.
Brivudine is a highly potent antiviral drug with good oral bioavailability and once-daily dosing. It has been shown to be 200-100 times more effective in inhibiting VZV replication than aciclovir.
It has been widely adopted in adult practice, but there is limited data from small studies in the immunocompromised paediatric cohort. Vogel et al. explored this in a larger prospective cohort study. They wanted to find out whether this oral drug offers effective HZ treatment in immunocompromised paediatric patients and whether it would be better than current intravenous aciclovir, enabling outpatient care.
Vogel C, Wetzel L, Wutzler P, Gruhn B. Treatment with brivudine in immunocompromised pediatric patients with herpes zoster. Chemotherapy. 2023; doi: 10.1159/000531034.
What did they look at?
This prospective cohort study looked at 64 immunocompromised children with lesions suspicious of zoster. The diagnosis was subsequently confirmed through testing vesicular fluid in 34 patients and blood samples in 16.
After the diagnosis was confirmed, patients were treated with brivudine, with a once daily dosing of 2mg/kg for at least seven days. Patients were monitored daily, and treatment was extended up to three weeks, depending on the regression of the rash.
Outcomes were: (1) crusting of the lesions; then (2) complete healing of lesions -the end goal of treatment.
Patients were offered additional drying preparations, antipruritics and analgesics, depending on need. As with all drug trials, patients were closely monitored for complications or adverse drug effects.
What did they find?
Of the 64 patients, 30 patients (46.9%) needed treatment for one week, 26 patients (40.6%) for two weeks, and the remaining eight patients (12.5%) needed up to 3 weeks of treatment. 16 patients declined supportive treatments, with 18 patients wanting drying preparations, eight patients receiving medication to reduce itching, and four patients requesting analgesia.
50 patients demonstrated full crusting within the first week of treatment, and the remaining 14 patients within the second week (figure 2). 17.2% had complete lesion healing within the first week, 60.9% during the second week, and 21.9% within the third week.
No patients experienced side effects during the study, and none suffered from post-herpetic neuralgia.
Limitations of the paper
The paper was a cohort study design. An RCT would have been a preferable trial design. Patients could have been split into two groups, comparing brivudine to a control group receiving conventional aciclovir. Small patient numbers would have made this tricky.
The study also lacked any statistical analysis, making it difficult to establish the significance of the results. Conclusions from the study, then, were more observational.
Furthermore, they did not perform a power calculation, making it harder to determine the true effectiveness of the drug.
Patients had different medical conditions leading to their immunocompromised state and were on different treatment-specific therapies. It is hard to know whether these could have altered the effectiveness of brivudine.
Just how good was the paper?- the CASP Checklist
Does the study address a clearly focused issue?
Yes, the study made its aims clear and tried to contribute data to an area of research where there is currently a paucity.
Was the cohort recruited in an acceptable way?
The patients were selected by purposive sampling. This ttechnique relies on the researcher’s judgement, making it subject to bias, affecting validity.
Was the exposure and outcome accurately measured to minimise bias?
There were no objective tests to confirm disease clearance. It was also unclear if one or several clinicians undertook these reassessments to ensure corroboration. It was not clear if there was any vested interest in ensuring a certain outcome.
These factors introduce considerable bias into the study.
Have the authors identified all important confounding factors?
Although the authors described the patient demographics, including age, gender and disease process, they didn’t undertake any statistical analyses to adjust for potential confounding factors.
Potential confounding factors such as ethnicity, socioeconomic status, severity of immunosuppression, underlying disease process or additional drug therapies were not accounted for.
Was the follow-up of the subjects complete and accurate?
Patients were monitored until the resolution of their Zoster.
No immediate or long-term side effects of the drugs were encountered. However, patients were only followed up for three months post-treatment. This may not have been long enough to discover any longer-term drug toxicities.
What were the results?
The vast majority of children responded promptly to brivudine. 78% showed crusting of lesions within a week. By week 2, 78% of patients had complete healing, with the remaining 12% better by week 3.
All patients were treated in an outpatient setting, and none needed admission. The researchers concluded that oral brivudine offers an effective, well-tolerated therapy in immunocompromised children and could be used as an outpatient treatment.
Do you believe the results?
This is a very small cohort study that could have been improved by undertaking a randomised control trial design. Statistical analyses were not performed to adjust for confounding factors or to assess the significance of the results. It is hard to interpret the validity of the conclusions.
Can the results be applied to your local population?
The results reflect a population within a Western setting. Due to the limited description of the socio-economic status, ethnicities, disease status and vulnerability of the patients, one cannot draw direct comparisons with my local patient cohort. A more detailed demographic description of the patients would help.
Do the results fit with other available evidence?
Brivudine is more established in the adult population. The conclusions of this study corroborate with three previous smaller studies (9-11) on immunocompromised children with HZ infection. Although two of these studies were small cohort studies, Heidl et al. randomised children to aciclovir or brivudine. Despite this more robust trial design, the significance of the results was limited by patient numbers and lack of power.
How does this impact your practice?
This is the largest study to date, highlighting that immunocompromised children with HZ infection can be treated with a once-daily dose of brivudine oral medication.
There are significant issues with the study, limiting its ability to change. practice.
The data highlights the need for larger, more robust studies in the form of randomised control trials. Patients receiving brivudine need to be followed up for longer in order to understand its safety profile better.
For now, use IV aciclovir as per your unit guidelines.
References
Bastard P, Galerne A, Lefevre-Utile A, Briand C, Baruchel A, Durand P et al. Different Clinical Presentations and Outcomes of Disseminated Varicella in Children With Primary and Acquired Immunodeficiencies. Frontier Immunology. 2022; 11:595478.
Patil A, Goldust M, Wollina U. Herpes zoster: A Review of Clinical Manifestations and Management. Viruses. 2022; 14(2):192.
Kuchar E, Szenborn L, Lis I, Jaroszewska A, Czeladzka J. Clinical Presentation of Herpes Zoster in Immunocompetent and Immunocompromised Hospitalized Children Treated With Aciclovir. Journal of paediatric haematology and oncology. 2016; 38(5):394-7.
Abdalla S, Briand C, Oualha M, Bendavid M, Béranger A, Benaboud S et al. Population Pharmacokinetics of Intravenous and Oral Aciclovir and Oral Valaciclovir in Pediatric Population To Optimize Dosing Regimens. Antimicrobial Agents and Chemotherapy. 2020; 64(12):e01426-20.
Andrei G, Snoeck R, Reymen D, Liesnard C, Goubau P, Desmyter J et al. Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus. European Journal of clinical microbiology and infectious diseases. 1995; 14(4): 318–329.
Vogel C, Wetzel L, Wutzler P, Gruhn B. Treatment with brivudine in immunocompromised pediatric patients with herpes zoster. Chemotherapy. 2023; doi: 10.1159/000531034. (Epub ahead of print)
Wassilew W, Wutzler P, Brivddin G. Oral brivudin in comparison with aciclovir for improved therapy of herpes zoster in immunocompetent patients: results of a randomized, double-blind, multicentered study. Antiviral Research. 2003; 59(1): 49–56.
Wutzler P, De Clercq E, Wutke K, Farber I. Oral brivudine vs intravenous aciclovir in the treatment of herpes zoster in immunocompromised patients: a randomized, double-blind trial. Journal of medical virology.1995; 46(3): 252–57.
Heidl M, Scholz H, Dörffel W, Hermann J. Antiviral therapy of varicella-zoster virus infection in immunocompromised children–a prospective randomized study of aciclovir versus brivudin. Infection. 1991; 19(6): 401–405.
Benoit Y, Laureys G, Delbeke M. J, De Clercq E. Oral BVDU treatment of varicella and zoster in children with cancer. European Journal of Pediatrics. 1985; 143(3): 198–202.
Rössig C, Ritter J, Jürgens H, Boos J. Prophylaxe und Therapie von Varicella-zoster- Virus-Infektionen bei immunsupprimierten Kindern. Monatsschrift Kinderheilkund. 1998; 146(3): 200–207.
