Cidofovir for Viral Infections in Immunocompromised Children: Guidance on Dosing, Safety, Efficacy, and a Review of the Literature.

OBJECTIVE: To describe the use of cidofovir (CDV) for viral infections in immunocompromised children (IC) and provide guidance on dosing and supportive care. DATA SOURCES: A PubMed search was conducted for literature published between 1997 and January 2022 using the following terms: cidofovir, plus children or pediatrics. STUDY SELECTION AND DATA EXTRACTION: Limits were set to include human subjects less than 24 years of age receiving intravenous (IV) or intrabladder CDV for treatment of infections due to adenovirus, polyomavirus-BK (BKV), herpesviruses, or cytomegalovirus. DATA SYNTHESIS: Data were heterogeneous, with largely uncontrolled studies. Conventional dosing (CDV 5 mg/kg/dose weekly) was commonly used in 60% (31/52) of studies and modified dosing (CDV 1 mg/kg/dose 3 times/week) was used in 17% (9/52) of studies, despite being off-label. Nephrotoxicity reported across studies totaled 16% (65/403 patients), which was higher for conventional dosing 29 of 196 patients (15%) than modified dosing 1 of 27 patients (4%). Saline hyperhydration and concomitant probenecid remain the cornerstones of supportive care, while some regimens omitting probenecid are emerging to target BKV. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: To our knowledge, this is the first comprehensive review of CDV use (indications, dosing, supportive care, response, and nephrotoxicity) in pediatric IC. CONCLUSIONS: Effective utilization of CDV in IC remains challenging. Further prospective studies are needed to determine the optimal CDV dosing; however, less aggressive dosing regimens such as modified thrice weekly dosing or low dosing once weekly omitting probenecid to enhance urinary penetration may be reasonable alternatives to conventional dosing in some IC.

Safety of Cidofovir Treatment for Suspected or Confirmed Adenovirus Infection in Immunocompetent Pediatric Population.

BACKGROUND: Cidofovir (CDV), a nucleoside phosphonate analogue, exhibits activity against severe cytomegalovirus and adenoviral (ADV) infection. Nevertheless, reports of elevated nephrotoxicity rates limited its use to highly vulnerable cases, mainly immunocompromised children with fulminant infection. Limited data exists regarding CDV safety in immunocompetent children. OBJECTIVE: To evaluate CDV-related toxicity, mainly nephrotoxicity, in immunocompetent children with severe ADV/cytomegalovirus infection. METHODS: We conducted a retrospective review of medical records for all immunocompetent children under 18 years of age treated with intravenous CDV from January 2005 to December 2019. RESULTS: Among the 23 patients identified, 21 were diagnosed with severe ADV infection. Median age was 15 months. Twenty-one (91%) children were admitted to the pediatric intensive care unit. Eighteen patients (78%) received standard CDV protocol (5 mg/kg CDV weekly for 2 weeks), 4 (17%) according to nephroprotective low-dose protocol and 1 patient transitioned. The median duration of CDV treatment was 14 days (range: 1-21 days). All patients received hyperhydration and probenecid with each infusion. Acute kidney injury was recorded in 1 patient (with concurrent septic shock) during CDV treatment. Two children exhibited acute kidney injury before CDV initiation, but renal function normalized during CDV treatment. One patient developed transient neutropenia (600 cells/L), apparently as a result of sepsis. No other major adverse effects were noted. Mortality rate was 3/23 (13%), unrelated to CDV toxicity. CONCLUSIONS: Our findings suggest that CDV-related nephrotoxicity rate in immunocompetent children may be lower than previously reported, perhaps lower than in the severely immunocompromised population.

Treatment of BK Polyomavirus-Associated Nephropathy in Paediatric Kidney Transplant Recipients: Leflunomide Versus Cidofovir.

OBJECTIVES: BK polyomavirus-associated nephropathy is a clinicopathological entity that negatively affects graft function in kidney transplant recipients. We compared the efficacy of leflunomide and cidofovir to treat BK polyomavirus-associated nephropathy in pediatric kidney transplant recipients. MATERIALS AND METHODS: Medical records of pediatric recipients with BK viremia for the period 2004 through 2019 were reviewed retrospectively, and patients diagnosed with BK polyomavirusassociated nephro-pathy were included in the study. A serum BK virus level above 104 copies/mL was accepted as BK viremia. We defined BK polyomavirusassociated nephropathy as detection of BK virus SV40 antigen on immunochemistry staining of renal graft tissue accompanied by signs of tubulointerstitial nephritis or elevated serum creatinine in addition to BK viremia. RESULTS: Of 304 kidney transplant recipients, 53 had persistent BK viremia; 36 of these patients (61.1% male) were included in the study with the diagnosis of BK polyomavirus-associated nephropathy. Twelve patients (33.3%) received cidofovir, and 14 (38.8%) received leflunomide. Results were similar between the cidofovir and leflunomide groups for serum creatinine level at last follow-up (0.91 ± 0.29 vs 0.94 ± 0.37 mg/dL, respectively; P = .843) and graft failure rate (8.3% vs 14.2%, respectively; P = .632). Graft failure was observed in 8.3% of patients with BK polyomavirus-associated nephropathy. CONCLUSIONS: Leflunomide and cidofovir showed similar efficacy for treatment of BK polyomavirus-associated nephropathy.

BILATERAL UVEITIS AND HYPOTONY FOLLOWING TREATMENT WITH TOPICAL CIDOFOVIR.

PURPOSE: To report a case of bilateral uveitis and hypotony associated with topical cidofovir treatment. METHODS: Case report. RESULTS: A 59-year-old diabetic man with HIV/AIDS presented with photophobia, ocular pain, and decreased vision. He was found to have bilateral hypotony, anterior uveitis, and serous choroidal detachments. Infectious disease workup, patient-reported history, and review of the patient's electronic medication list did not identify the etiology. Treatment with intensive topical corticosteroids led to resolution of uveitis and choroidal effusions within 3 months and resolution of hypotony within 9 months. Two years after his initial presentation, the patient developed acute recurrence of bilateral hypotony, anterior uveitis, and serous choroidal detachments shortly after intravenous cidofovir treatment. Careful reevaluation of the patient's outside medical records revealed that he had initiated treatment for rectal herpes simplex virus with compounded topical cidofovir one month before his initial presentation. CONCLUSION: To our knowledge, this is the first reported case of topical cidofovir causing ocular toxicity. Compounded and topical medications, like cidofovir in this case, may not appear on a patient's electronic medication list, so a focused review of outside medical records may be beneficial when a particular medication toxicity is suspected.

Cidofovir-induced anterior uveitis in an allogeneic stem cell transplant recipient.

Anterior uveitis is a reported complication of intravenous cidofovir, almost exclusively described in human immunodeficiency virus (HIV) infected patients treated for cytomegalovirus retinitis. In this study, we report the case of an allogeneic stem cell transplant recipient with significant visual impairment and hypotony following administration of high-dose intravenous cidofovir for hemorrhagic cystitis due to BK virus.

Evaluation of Safety of Intralesional Cidofovir for Adjuvant Treatment of Recurrent Respiratory Papillomatosis.

Importance: The use of intralesional cidofovir injections for recurrent respiratory papillomatosis (RRP) remains controversial owing to concern regarding the risks of its use, including increased risk of dysplasia or carcinogenesis. Objective: To describe the rates of dysplasia, development of malignant lesions, and adverse events associated with use of intralesional cidofovir injections as adjuvant treatment for RRP compared with patients treated without adjuvant cidofovir. Design, Setting, and Participants: In this case series performed at a tertiary care referral center, review of electronic medical records on all adult and pediatric patients (N = 154) treated for RRP with adequate follow-up from January 1, 2000, to December 31, 2016, was performed. Data were collected on the use of cidofovir, development and presence of dysplasia or malignant lesions, complications, and intersurgical interval. Exposures: Adjuvant intralesional cidofovir or surgical excision only. Main Outcomes and Measures: The main outcomes measured were the development of dysplasia, malignant lesions, and complications from treatment. These outcomes were determined before collection of data. Results: Of the 154 patients included in the analysis, 83 patients (53.9%) received adjuvant intralesional cidofovir and 71 patients (46.1%) underwent surgical excision only. One hundred patients (64.9%) were male; mean age was 27.7 (95% CI, 24.3-31.2) years. Patients were followed up for a median (interquartile range) of 70 (24-118) months in the noncidofovir group and 91 (47-152) months in the cidofovir group. There were no statistically significant differences in the rates of development of dysplasia (2.8%; 95% CI, -8.3% to 13.2%) or malignant lesions (2.2%; 95% CI, -5.3% to 11.2%) between the groups. No nephrotoxic effects were observed in the treated cohort, and only 5 minor complications that occurred in 628 injections were noted in the cidofovir group; 3 were related to direct laryngoscopy and 2 were related to needle malfunction. Conclusions and Relevance: In this cohort of patients with RRP, adjuvant intralesional cidofovir injections did not appear to cause major complications or an increased rate of development of dysplasia and cancer.

Drug-induced Uveitis in HIV Patients with Ocular Opportunistic Infections.

Purpose: To describe drug-induced uveitis in immunocompromised patients diagnosed with Human Immunodeficiency Virus (HIV) infection Methods: Narrative Review Results: Systemic and intraocular medications administered for the treatment of acquired immune deficiency syndrome (AIDS)-associated diseases in patients infected with HIV are a well-known cause of uveitis. Conclusions: Cidofovir and rifabutin, among other novel anti-retroviral therapies, are strongly associated with drug-induced uveitis. It is imperative to understand the pathogenesis, clinical findings, and management of HIV patients with uveitis induced by these agents.

Neutropenia and renal dysfunction due to intravesical cidofovir for virus-associated hemorrhagic cystitis after kidney and allogenic hematopoietic stem cell transplantations.

We present a patient with virus-associated hemorrhagic cystitis who underwent kidney and allogenic hematopoietic stem cell transplantations (allo-HSCT). Six months post-allo-HSCT, adenovirus hemorrhagic cystitis occurred, which has been in remission after a single dose of intravesical cidofovir. This might cause prolonged neutropenia and nephrotoxicity, suggesting cidofovir absorption in the blood.

Hemoptisis y bronquiolitis obliterante en niños con papilomatosis laríngea recurrente: reacciones adversas al cidofovir nebulizado / Hemoptysis and Bronchiolitis Obliterans in Children with Recurrent Respiratory Papillomatosis: Adverse Reactions to Nebulized Cidofovir

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Model of population pharmacokinetics of cidofovir in immunocompromised children with cytomegalovirus and adenovirus infection.

Objectives: To describe cidofovir pharmacokinetics and assess the link between concentration and safety/efficacy in children. Patients and methods: An observational study was conducted in 13 immunocompromised children receiving cidofovir for adenovirus and/or cytomegalovirus infection. A population pharmacokinetic model was built and AUC0-24 was derived for each patient. Virological success was defined as a decrease of the viraemia by ≥1 log10 copies/mL within 15 days of cidofovir initiation. The association between AUC0-24 and virological success was assessed using a Wilcoxon test. An AUC0-24 cut-off value was determined using a Fisher's exact test. Results: Overall, 86 blood samples were analysed. A two-compartment model with first-order absorption and elimination best described the cidofovir data. Virological success (VS) was reached in 6/8 children with adenovirus viraemia and in 1/4 children with cytomegalovirus viraemia. Patients with VS displayed a non-significant higher median AUC0-24 compared with patients with virological failure: 48.6 (range 8.9-72.6) versus 19.1 (6.9-22.7) mg·h/L. Adenovirus-viraemic patients with an AUC0-24 value below 19.1 mg·h/L had a higher probability of treatment failure (P = 0.03). Aviraemic children with stool and/or nasopharyngeal adenovirus carriage cleared the viral carriage within a month of cidofovir initiation. During treatment, 1/13 children developed a tubulopathy but none of them had an increase in creatininaemia. Conclusions: Cidofovir appears safe and reasonably well tolerated and seemed to have efficacy in a subset of patients with adenovirus/cytomegalovirus infection. Therapeutic drug monitoring may be useful in children receiving cidofovir and, in the case of adenovirus infection, targeting an AUC0-24 above 19.1 mg·h/L could be associated with higher probability of virological success.

Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multicentre, randomised, phase II trial (RT3VIN).

OBJECTIVE: To compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3. DESIGN: A prospective, open, randomised multicentre trial. SETTING: 32 general hospitals located in Wales and England. POPULATION OR SAMPLE: 180 patients were randomised consecutively between 21 October 2009 and 11 January 2013, 89 to cidofoovir (of whom 41 completely responded to treatment) and 91 to imiquimod (of whom 42 completely responded to treatment). METHODS: After 24 weeks of treatment, complete responders were followed up at 6-monthly intervals for 24 months. At each visit, the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was assessed and any new lesions were biopsied for histology. MAIN OUTCOME MEASURES: Time to histologically confirmed disease recurrence (any grade of VIN). RESULTS: The median length of follow up was 18.4 months. At 18 months, more participants were VIN-free in the cidofovir arm: 94% (95% CI 78.2-98.5) versus 71.6% (95% CI 52.0-84.3) [univariable hazard ratio (HR) 3.46, 95% CI 0.95-12.60, P = 0.059; multivariable HR 3.53, 95% CI 0.96-12.98, P = 0.057). The number of grade 2+ events was similar between treatment arms (imiquimod: 24/42 (57%) versus cidofovir: 27/41 (66%), χ2 = 0.665, P = 0.415), with no grade 4+. CONCLUSIONS: Long-term data indicates a trend towards response being maintained for longer following treatment with cidofovir than with imiquimod, with similar low rates of adverse events for each drug. Adverse event rates indicated acceptable safety of both drugs TWEETABLE ABSTRACT: Long-term follow up in the RT3VIN trial suggests cidofovir may maintain response for longer than imiquimod.