Cidofovir in the Management of Adenovirus and Polyoma (BK) Virus Infections in Paediatric Oncology including BK virus associated Hemorrhagic Cystitis - Guidelines for the use of

Publication: 22/01/2016  --
Last review: 01/04/2019  
Next review: 01/04/2021  
Clinical Guideline
CURRENT 
ID: 4455 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2019  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guidelines for the use of Cidofovir in the Management of Adenovirus and Polyoma (BK) Virus Infections in Paediatric Oncology including BK virus associated Hemorrhagic Cystitis

Summary of Guideline

Diagnosis of adenovirus or polyoma virus is made by PCR (polymerase chain reaction). This guideline does not cover the diagnostic criteria.

Once a diagnosis has been made and a decision has been taken to treat, there are different strategies depending on the location of the infection and the clinical status of the patient. This guideline provides a treatment algorithm to establish the most appropriate management strategy and gives clear guidance on supportive care if required.

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Aims

  • To provide a treatment algorithm for the appropriate use of cidofovir in Adenovirus and Polyoma virus infections.
  • To provide guidance on the administration and supportive care required when prescribing cidofovir

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Diagnosis

The diagnosis of adenovirus and Polyoma virus is confirmed by PCR. The viruses may be detected in many areas such as the blood, urine, nasopharyngeal aspirate (NPA), stools.
As both viruses are commonly occurring in the natural population, it is not uncommon for this patient population to test positive for these infections.
Bearing this in mind, both viral load and clinical condition should be taken into consideration when making the decision to start anti-viral therapy.

The decision to treat is made by the responsible consultant. Treatment may be pre-emptive, for example, if there are two consecutive adenovirus PCR results of >5000 copies/ml; or, it may be active therapy, for example, on the finding of a positive urine + blood BK virus result in the context of haemorrhagic cystitis.

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Investigation

Prior to starting cidofovir the following clinical investigations are required:

  • Confirmed adenovirus/polyoma virus infection
  • Urea and electrolytes
  • Estimated GFR. If GFR is less than 55mls/min/1.73m2 then a discussion must occur with the consultant regarding the suitability of intravenous cidofovir. (1)
  • Identification of concurrent nephrotoxic treatment (if applicable)
  • Review of previous renal function- any episodes of renal impairment?
  • Bicarbonate
  • Urine dipstick for protein. If 2+ proteinuria, discuss with consultant.
  • Assessment of fluid balance and fluid allowance

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Treatment / Management

* Good renal function is defined in the summary of product characteristics as CrCl>55mls/min. This should be used as a guide when deciding on a dosing strategy, though each patient should be considered individually depending on the clinical situation. There is no defined lower limit of CrCl for the 1mg/kg schedule and this should be considered on an individual basis with consideration given to the risk/benefit in a life threatening situation.

Hydration.

The administration of concurrent hydration sodium chloride 0.9% and probenecid is essential to reduce the potential nephrotoxicity associated with cidofovir. Before prescribing fluids, a careful assessment should be made regarding the patient’s fluid balance and total daily fluid allowance.

Note: Hydration is not required when cidofovir is given via the intravesicular route.

Sodium chloride 0.9% is used to promote better diuresis.

Hydration schedule

16 years and above:
1000ml immediately prior to the cidofovir (over 1 hour) and if tolerated, another 1000ml after the end of the cidofovir infusion (over 1-3 hours) (1)

Less than 16 years:
15mls/kg immediately prior to the cidofovir (over 1 hour) (max 1000ml)
15mls/kg after the end of the cidofovir (over 1-3 hours) (max 1000ml)

These hydration schedules are based on the 5mg/kg weekly dose. There are no specific modified fluid schedules to reflect the fractionated 1mg/kg dosing therefore the above schedules should be used but potentially modified depending on clinical status and urine output.

Often these groups of patients are unwell with poor urine output or fluid balance problems. Careful consideration must be given to the volume of fluid suitable for the patient against the potential nephrotoxicity of the drug. Fluid modification may be required sometimes and this should always be after discussion with a consultant.

Probenecid Schedule

Probenecid is only available as tablets therefore should be dispersed in a suitable quantity of water if the patient is not able to swallow tablets. (Note: any volume of water which allows adequate dissolution of the tablet is appropriate)

Dose:

Weight (kg)

Total probenecid dose

<20kg

1g total (500mg, 250mg, 250mg)

21-40kg

2g total (1g, 500mg, 500mg)

41-60kg

3g total (1.5g, 750mg, 750mg)

16 years and above or >61kg

4g total (2g, 1g, 1g)

Summary of administration

T=0 Probenacid (oral)
T=2 Hydration (over 1 hour)
T=3 Cidofovir (over 1 hour)
T=4 Hydration (over 1-2 hours)
T=6 Probenacid (oral)
T=12 Probenacid (oral)

Administration of intravenous cidofovir

Cidofovir is prepared in 50-100ml sodium chloride 0.9% and should be infused over ONE hour. (Concentration range 0.2-8.1mg/ml)

Administration of intravesicular cidofovir

Cidofovir is instilled in the bladder for topical action. To ensure adequate contact with the bladder wall, the optimum volume for instillation is 100ml. This is supplied in either 1x100ml urotainer (or possibly 2x50ml urotainer to be instilled consecutively). In the exceptional situation where urotainer use is not possible, please discuss other options with the ward pharmacist.To ensure adequate contact time, the instillation should be left in for up to 60 minutes.

This should be prescribed as xmg in 100ml. Please supply in 1x 100ml or 2x50ml urotainer for bladder instillation. (The size of urotainer used depends on the available stock in aseptics.)

Occasionally individual patient factors prevent the administration as described above so it may be necessary to reduce the volume to 50ml or reduce the instillation time. This should be discussed with the patient’s consultant.

Side effects (1)

System Organ Class

Adverse reactions

Blood and lymphatic system disorders

Very common

Neutropenia

Nervous system disorders

Very common

Headache

Eye disorders

Common

Iritis, uveitis, hypotony of the eye

Ear and labyrinth disorders

Not known

Hearing impaired

Respiratory, thoracic and mediastinal disorders

Common

Dyspnea

Gastrointestinal disorders

Very common
Common
Not known

Nausea, vomiting
Diarrhoea
Pancreatitis

Skin and subcutaneous tissue disorders

Very common

Alopecia, rash

Renal and urinary disorders

Very common
Common
Uncommon

Proteinuria, blood creatinine increased
Renal failure
Fanconi syndrome acquired

General disorders and administration site conditions

Very common

Asthenia, fever, chills

Should severe side effects develop, Consultant advice should be sought and specialist review (e.g. ophthalmology for uveitis) requested.

Contraindications and cautions (1) 

  • GFR<55mls/min/1.72m2
  • Proteinuria equal to or more than 2+.
  • Concurrent nephrotoxic drugs.
Estimated GFR = 40 x height (cm)
creatinine (micromol/L)

Interactions (1) 

  • Tenofovir disoproxil fumarate
  • Probenecid is known to increase the exposure of many substances (e.g., paracetamol, acyclovir, angiotensin-converting enzyme inhibitors, aminosalicyclic acid, barbiturates, benzodiazepines, bumetanide, clofibrate, methotrexate, famotidine, furosemide, nonsteroidal anti-inflammatory agents, theophylline, and zidovudine). Care should be given when prescribing any of these agents concurrently.

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Provenance

Record: 4455
Objective:
  • To provide evidence-based recommendations for the management of Adenovirus and Polyoma virus with cidofovir.
  • These guidelines do not cover the diagnosis and symptomatic management of these viral infections.
Clinical condition:

Adenovirus and Polyoma virus Infection

Target patient group: Paediatric and Teenage and Young Adult Oncology
Target professional group(s): Pharmacists
Secondary Care Doctors
Adapted from:

Evidence base

References

  1. Summary of Product Characteristics last updated on the eMC: 07/04/2011. Accessed Jan 23rd 2013
  1. Cesrao et al. Cidofovir for BK virus-associated haemorrhagic cystitis: a retrospective study. Clin Infect Dis 2009 Jul 15;49(2)233-40

  2. Gaziev et al. Late-onset haemorrgaic cystitis in children after haematopoietic stem cell transplantation for thalassemia and Sickle cell anaemia: A Prospective Evaluation of Polyoma (BK) virus Infection and Treatment with Cidofovir Biology of Blood and Bone Marrow Transplantation 2010 May;16(5):662-671. 2009 Dec 22.

  3. Harkensee et al. Prevention and management of BK-virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation- a systematic review and evidence-based guidance of clinical management. British journal of Haematology 142 717-731

  4. Fanourgiakis et al. Intravesical Instillation of Cidofovir in the Treatment of Haemorrhagic cystitis caused by Adenovirus type II in a Bone marrow Transplant Recipient. Clinical Infectious Diseases 2005;40:199-201

  5. Bridges et al Cidofovir Bladder Instillation for the Treatment of BK Haemorrhagic Cystitis after Allogeneic Stem Cell Transplantation. American Journal of Haematology 81:535-537 (2006)

  6. Walden et al. Intravesical cidofovir-instillation therapy for polyomavirus-associated haemorrhagic cystitis after bone marrow transplantation. Urologe A 2007 May;46(5)535-7

Evidence levels:
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

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Background

Cidofovir has been used historically for the management of cytomegalovirus (CMV) induced retinitis. Over the past few years there has been an increased usage for the management of adenovirus and polyoma virus. The licensed dose is 5mg/kg weekly but due to the serious nephrotoxicity observed with this dose, alternative dosing strategies have been introduced over the years. This guidelines aims to review the evidence for these new dosing strategies and to provide a safe and effective regime giving appropriate and clear guidance about the implementation of these strategies.

Cesaro et al conducted a retrospective study on the safety and outcome of cidofovir treatment for patients with BK virus (BKV) in centres affiliated with the European Group for Blood and Marrow transplantation. They reviewed 62 patients with a diagnosis of BKV haemorrhagic cystitis (HC), of whom 92% (57) received cidofovir intravenously and 8% (5) received cidofovir intravesically. Complete response was noted in 67% of the patients treated intravenously and in 60% of the patients treated intravesically. A partial response was noted in 12% of those treated intravenously and 20% of those treated intravesically. After a median follow up of 287 days, overall survival was 63% in the complete response (CR) group compared to 14% in the partial response (PR) or no response (NR) group (p=0.001) and the total treatment related mortality was 40% in those reporting a CR and 72% in those reporting a PR or NR (p=0.001). (2)(B)

Gaziev et al conducted a prospective evaluation of Polyoma (BK) virus infection and treatment with cidofovir in children following stem cell transplantation (SCT). 30 patients developed grade II to IV toxicity. Patients were given 1.5mg/kg/day three times a week or 5mg/kg weekly. The median duration of therapy was 27 days, and a median of 9 doses were given. All patients had a complete clinical response and 69% had a microbiological response at 4 weeks. (3)(B)

Harkensee et al completed a systematic review and produced evidence based guidance for clinical management for the prevention and management of BK virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation (HSCT). On review of medical interventions, they concluded that cidofovir has the highest specificity against BK virus, though significant nephrotoxicity often precludes its use. No randomised control trial has yet been undertaken in paediatrics post HSCT, though it is widely used for this indication. They reviewed a prospective case series by Gorczynska et al which observed a cohort of 102 HSCT paediatric patients with viral associated HC. 22 patients were given cidofovir at a dose of 5mg/kg initially twice weekly then weekly, leading to complete eradication from the blood. No nephrotoxicity was observed. (4)(A)

The references below support the use of cidofovir as a bladder instillation.

Fanourgiakis et al reviewed a case report of a 34 year old man who was admitted with renal insufficiency and haemorrhagic cystitis day 105 post HSCT. PCR was positive for BK virus in his urine. This then became negative but symptoms continued and the patient was positive for adenovirus. Continuous bladder irrigation was instigated but there was no improvement in the patient. As the patient was in renal failure, the decision was taken to administer the cidofovir topically. A dose of 5mg/kg in 100ml was instilled slowly and clamped for I hour. There was marked improvement of the symptoms the next day, and 4 days later the cultures became negative. (5)(C)

Bridges et al review the case of a 25 year old male who under went an allogeneic MUD SCT. He developed asymptomatic haematuria on D+22 and PCR showed the urine positive for BK virus. On D+49, his haematuria worsened with the formation of large clots and also pain and abdominal cramps. Hyper hydration and bladder irrigation were initiated. His symptoms then continued to worsen and he was requiring 3-4 transfusions a week. On D+76, 5mg/kg of cidofovir was instilled in to his bladder for 1 hour then allowed to drain. Within 3 days the clots and haematuria had improved. A second dose was given 1 week later. On day +98 he was no longer transfusion dependant and his viral load on PCR had significantly reduced. He was then able to go home. Unfortunately he then relapsed and died on D+190. (6)(C)

Walder et al also report a case of a 14 year old boy with haemorrhagic cystitis post SCT. Irrigation and hydration were not sufficient to control symptoms and cidofovir was instilled into the bladder to treat the suspected BK virus. Gross haematuria resolved within a few days. (Article in German) (7)(C)

Supportive care is also paramount in reducing renal toxicity therefore this guidance will draw together the different hydration strategies to provide a safe evidence based schedule for the administration of hydration.

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