Cidofovir Therapy Research Articles

Therapeutic strategies against BK polyomavirus infection in kidney transplant recipients: Systematic review and meta-analysis

BackgroundThe selection of antiviral therapy for BK polyomavirus (BKPyV) infection has been extensively debated. Our study aimed to assess the efficacy and safety of various treatments for BKPyV infection. MethodsWe searched PubMed, EMBASE, and Web of Science databases for relevant studies regarding drug treatments for BKPyV viremia/DNAemia published between January 1, 1970 and September 30, 2022. Two independent authors screened the published studies, extracted pertinent data, and evaluated their methodological quality. A meta-analysis was performed using the RevMan software version 4.2.2. ResultsA total of 33 published studies involving 986 patients were included in the meta-analysis. Overall, therapeutic interventions comprised immunosuppression reduction alone or in combination with leflunomide, intravenous immunoglobulin (IVIG), cidofovir, or mTOR inhibitor (mTORi) therapy. The meta-analysis revealed that the efficacy of immunosuppression reduction alone for serum BKPyV clearance was 68% (95% confidence interval [CI]: 0.58–0.77; I2 = 78%). Moreover, the efficacy of immunosuppression reduction in combination with leflunomide, cidofovir, IVIG, or mTORi therapy for serum BKPyV clearance was 61% (95% CI: 0.47–0.74; I2 = 83%), 71% (95% CI: 0.63–0.78; I2 = 0), 87% (95% CI: 0.82–0.93; I2 = 45%), and 80% (95% CI: 0.59–1.00; I2 = 58%), respectively. Compared to immunosuppression reduction alone, immunosuppression reduction combined with IVIG therapy offered a statistically significant benefit in serum BKPyV clearance (P < 0.01) with minimal adverse reactions, whereas other adjunctive drug treatments did not demonstrate considerable effects. ConclusionsReducing immunosuppression remains the primary approach for treating BKPyV infection. Although the combination treatment with IVIG proved to be most effective, other agents might offer varied antiviral advantages of high heterogeneity, which should be substantiated in future long-term randomized controlled trials.

Maymun Çiçeği Virüsüne Karşı Antiviral Yaklaşım ve Bağışıklık

İnsan maymun çiçeği, çift sarmallı DNA (dsDNA) virüslerinin Poxviridae ailesindeki Orthopoxvirus cinsinin bir üyesi olan maymun çiçeği virüsünün neden olduğu zoonotik bir enfeksiyondur. İlk olarak 1970 yılında Demokratik Kongo Cumhuriyeti'nde dokuz aylık bir bebekte tanımlandı. O zamandan beri, Orta ve Batı Afrika'da ve bazen Avrupa ve Kuzey Amerika'da beş salgınla sonuçlandı. Endemik bölgelerdeki insan enfeksiyonları, enfekte hayvanlarla avlanma ve deri yüzme yoluyla yakın temas veya evde kemirgen istilası ile ilişkili olarak tanımlanmıştır. İnsandan insana bulaşma, özellikle çiçek hastalığına karşı aşılanmamış olanlar arasında, indeks vakaların ev temaslılarında da tanımlanmıştır. Bulaşma yolları, tükürük, solunum salgıları, cilt lezyonları, vücut sıvıları veya kontamine cisimlerle temasdır. Çiçek hastalığının eradikasyonundan ve rutin çiçek aşısından sonra Maymun çiçeği hastalığına karşı duyarlı konaklarda artış izlenmiştir. Çiçek aşısının maymun hastalığına karşı %85 koruma sağladığı tahmin edilmektedir. Maymun çiçeği virüsü hastalığı (MÇVH) hastaların çoğunda medikal tedavi ile birlikte iyileşmektedir. Semptomları hafifletmek, komplikasyonları azaltmak için klinik bakım ve destekleyici tedavi verilmelidir. Kusma, ishal gibi sıvı kayıplarının olduğu gastrointestinal semptomları olan hastalara oral ya da intravenöz sıvı tedavisi gerekmektedir. Sekonder bakteriyel enfeksiyon izlendiği durumlarda etkene özgü ve uygun antibiyotik tedavisi verilmelidir. Atipik bölgelerdeki (örneğin ağız, gözler, genital bölge) maymun çiçeği enfeksiyonu için tedavi de düşünülebilir. Bir takım ilaçlar denenmiştir ama etkinliği net değildir. Etkinliği olabileceği düşünülen antiviraller; Tecovirimat (TCV), brincidofovir (BCV) ve cidofovir (CDV)’ dir. Bazı uzmanlar şiddetli hastalığı olan hastalarda TCV ve CDV ile ikili tedavi önerebilse de, şu anda TCV tercih edilen tedavidir. MÇVH riskini azaltabilecek iki mevcut aşı vardır. Yüksek risk maruziyeti olan bireylere temas sonrası 14 gün içinde aşılama önerilir. Maruziyet sonrası aşılama, düşük risk maruziyeti olanlar için endike değildir.

Cidofovir, a Choice for Salvage Treatment of CMV Infection in the Patients with Haploidentical Hematopoitic Stem Cell Transplantation

Cidofovir (CDV) is a nucleotide analogue with broad antiviral activity and has been approved for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome. Data on the use of CDV for anti-CMV treatment in the patients with haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is rare. In this study, 31 (defined as CDV-second line treatment, ST group) out of 101 (conventional treatment, CT group) haplo-HSCT recipients with CMV infection being front-line treated with intravenous ganciclovir (GCV) or foscarnet (FSC) between the year 2017 and 2019, failed or intolerated to the preemptive antiviral therapy, and were switched to CDV therapy. Also, another 9 (CDV-front line treatment, FT group) patients with CMV infection were preemptively treated with CDV. CDV was used at a dose of 5 mg/kg per week until CMV-DNA negative twice with quantification polymerase chain reaction (qPCR) detection or disease progression. 23/28(82.1%) patients achieved treatment response with a median response time of 9(2-23) days and 20/28(71.8%) obtained complete response (CR) in CDV-ST group. While 6/8(75.0%) acquired CR with a median time of 6 (4-25) days in CDV-FT group. Higher response rate was seen in CDV treatment groups, though not significantly different, when being compared with those in CT groups (66/95(69.5%), 7 (2-34) days, 65(68.4%, respectively, all P-value &amp;gt;0.05). Also, there was not statistical difference in CMV-related mortality among the three groups (P-value &amp;gt;0.05). With a median follow-up of 10 (1-28) months, cumulatively 8/22(36.3%) patients experienced CMV reactivation in CDV-ST group, while 23/62(37.0%) happened in CT group, there was not significant difference (P&amp;gt;0.05). Whereas none with CMV recurrence was observed in the CDV-FT group. CDV-related toxicities were recorded in a total of 13/40 (32.5%) patients, shown as 7(17.5%) with I~II° gastrointestinal side effects, 6(15%) presenting reversible nephrotoxicity. Taking together, salvage treatment with CDV shows no worse efficacy than ganciclovir or foscarnet does in the front line treatment of CMV infection in haplo-HSCT recipients. Also, CDV-related toxicity is tolerated. Keywords: cidofovir, CMV infection, haplo-hematopoietic stem cell transplantation, efficacy, safety Disclosures No relevant conflicts of interest to declare.

Safety Profile and Efficacy of Cidofovir for Adenovirus in Pediatric Stem Cell Transplant Recipients Following Reduced-Intensity Conditioning

Background Adenovirus (ADV) infection remains a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in the pediatric population. Pre-emptive monitoring by polymerase chain reaction (PCR) assay for ADV viremia in high risk patients permits prompt initiation of therapy. Cidofovir (CDV) is a nucleotide analogue which is utilized for treatment of ADV infections in immunocompromised patients; however, CDV can be associated with substantial dose-dependent nephrotoxicity. The use of reduced intensity conditioning (RIC) has invariably necessitated the use of anti-thymocyte globulin or alemtuzumab for rejection prophylaxis, putting patients at higher risk for viral infections. We report our single-center experience with CDV for treatment of ADV infection in 20 allo-HSCT patients. Methods We performed a retrospective review, from 2012-2019, of children with non-malignant diseases that received RIC with alemtuzumab, fludarabine, melphalan, and thiotepa. ClinicalTrials.gov Identifier: NCT01962415 Recipients of CDV were identified and reviewed for ADV PCR results (blood, stool, urine, respiratory viral panel), CDV course characteristics (mg/kg dose, frequency, and duration), and changes in renal function. All patients received a combination of probenecid and hydration to reduce nephrotoxicity. Results A total of 25 CDV courses, in 20 patients (median age: 4 years, range 0.6-22) were identified. Of the 20 patients, 18 patients (90%) received umbilical cord blood as their graft source. Of the 25 courses prescribed, 20 courses (80%) were in patients with a positive blood ADV PCR, and 19 courses (76%) with a positive stool ADV PCR. Typically, 5 mg/kg/dose (range 1-9) was given weekly, then every 2 weeks once viral load declined. The median number of doses of CDV was 8 doses (range 2-32) with treatment duration ranging from 7-169 days. Renal dysfunction with CDV appeared to be reversible, with 14 courses (56%) having peak serum creatinine (SCr) >50% of baseline during CDV treatment, though average rise in SCr when comparing baseline to CDV discontinuation values was 20%. Only 2 courses had a peak SCr ≥ 1 mg/dL during CDV treatment. In 16 courses (64%) CDV therapy was discontinued due to clinical resolution, PCR negativity, or a combination of both, in 6 courses (24%) patients were switched to brincidofovir, and in 1 course (4%) the patient transferred care. 18 of 20 are alive, one child died of complications of multiple infections including ADV, and another due to accelerated CNS demyelination. Conclusion CDV appeared remarkably safe and effective post RIC conditioning. Prospective screening allowed for early initiation of CDV and limiting poor outcomes associated with ADV.

First Reported Use of Artesunate Adjunctive Therapy for Severe BK Polyoma Virus Hemorrhagic Cystitis (BKPyV-HC)

BKV is ubiquitous with 80-90% seropositivity. BKV establishes latency in kidney tubular epithelial/urothelial cells but is shed in urine. Reactivation may cause interstitial nephritis (BKV-IN) after renal transplant (Ktxp) and hemorrhagic cystitis (HC) and/or BKV-IN after allo-HSCT. BKV-HC occurs 2-8 wks after HSCT. Diagnosis requires: cystitis, macroscopic hematuria and urine (U) BK VL >7log10 copies/ml. High-level BK viruria occurs in >80% post allo-HSCT but only 5-20% develop HC. Plasma (PL) VLs are elevated in 60% and declining PL-VL correlates with improvement. Re-activation risk factors include young age, male sex; high risk donor; HSCT conditioning with CTX, busulfan, TBI; and grade 2-4 GVHD. Therapy is supportive. There are no FDA approved agents for BKV. Cidofovir (CDV), leflunomide, and FQs have in-vitro BKV activity but clinical use is not supported by rigorous trials. Pooled IVIg contains BKV antibodies. Reduction of immunosuppression improves BKV-IN in Ktxp recipients but is ineffective in allo-HSCT BKV-HC. For >30 years 1st line therapy for malaria has been Artesunate (ART), an artemisinin derivative with a good safety profile. ART has an antiviral spectrum including herpesviruses, HBV, HCV, HIV and BKV. ART inhibits BKV replication in human renal tissue culture via activation of transcription factors NF-κB / Sp-1 and concentration dependent down regulation of phosphorylation by kinase PI3K without cellular cytotoxicity. In-vitro, ATV is synergistic and/or additive with CDV, GCV and Maribavir. Case reports/series of ART use in CMV, HHV6, and resistant HSV-2, are published. CASE: A 22yo M w R/R (see table) T/HRLBCL IIIB underwent a haplo-SCT in PR. At week +8 he developed gross hematuria, cystitis (9-10/10 pain), and urinary outlet obstruction. U-/PL-BK VLs were >100,000,000/ 7.9 mg/dl). PL-BKV VL rose to 196,537copies/ml and both ureters obstructed necessitating bilateral nephrostomy drains. We requested ART via an eIND from the FDA and current US manufacturer. ART load (2.4 mg/kg IV Q 12H x2) followed by 2.4 mg/kg/d administered x 14 d. Cystitis pain fell from 9-10 to 0-2/10 by day 4. U-/PL-BKV VLs fell to 91,980 / There was a strong temporal association between ART treatment and clinical response. CDV and IVIg therapy may also have contributed to the observed improvement. ART therapy may be an emerging option for BKV-IN and HC and further research is warranted.

Viral Kinetics and Outcomes of Adenovirus Reactivation Following Allogeneic Hematopoietic Cell Transplant or CAR-T Cell Therapy

Adenovirus (AdV) viremia occurs in up to 10% of patients following allogeneic hematopoietic cell transplant (HCT). Although AdV disease can be severe and associated with high mortality among those with pneumonia or disseminated disease, little is known about the viral kinetics of AdV and the natural history of untreated viremia following HCT or CAR-T cell therapy. Cidofovir is the only available therapy for AdV and is associated with significant toxicity. Thus, establishing an optimal threshold for pre-emptive therapy is urgently needed. To bridge this gap in knowledge, we conducted a retrospective study of 18 allogeneic HCT or CAR-T cell recipients with documented AdV viremia treated at our center between 12/2014 and 7/2019. Median follow up time was 102 days (IQR 56 - 318). The median absolute lymphocyte count (ALC) at time of AdV reactivation was 425 (IQR 124 - 695) for HCT and 425 (IQR 410 – 440) for CAR-T cell patients. 12/18 (67%) of the patients received corticosteroids within 30d prior to AdV (median prednisone dose 33.75 mg/d). The median time to AdV reactivation after HCT was 176 days (IQR 77 - 424), and after CAR-T cell was 366 days (IQR 173 to 558). Median initial VL was 1100 copies/mL (IQR 263 – 4000). Median peak viral load was 79,550 copies/mL (IQR 2,225 - 243,750). 11 (61%) patients received cidofovir therapy, even though, except for 2 cases of possible cystitis, 16/18 (89%) were asymptomatic at the time of AdV viremia. Median duration of viremia was 23 days for treated and 13 days for untreated patients. Among treated patients, median duration of viremia was shorter when treatment was initiated at viral loads All-cause mortality was 44%. Median time to death after AdV diagnosis was 59 days. Only 1 of 7 (14%) patients (included 5 untreated patients) with peak viremia The median AdV DNA level prior to initiation of therapy was 126,000 copies/mL (IQR, 7200-610,500). The median duration of treatment was 16 days (IQR 9 - 34). 4/11 (36%) patients treated with cidofovir had acute kidney injury (AKI) while on therapy. Median cumulative cidofovir dose was higher in patients who developed AKI vs those who did not, but this finding didn't reach statistical significance (25 vs 15mg/kg; P=0.18). In conclusion, AdV viremia is associated with high all-cause mortality, especially among those with viral loads >10,000 copies/mL. Delaying initiation of therapy until AdV ≥10,000 copies/mL is associated with more protracted viremia and longer courses of antivirals with associated nephrotoxicity. Although larger studies are needed, an AdV viral load >10,000 copies/mL following allogeneic HCT and CAR-T cell is a reasonable cutoff for initiation of pre-emptive antiviral therapy

Epidemiology and Outcomes of Early-Onset and Late-Onset Adenovirus Infections in Kidney Transplant Recipients.

ObjectiveAdenovirus (ADV) infection after kidney transplantation (KT) causes significant morbidity. Patient characteristics and outcomes of ADV infection in KT recipients were investigated.MethodAll adult KT recipients with ADV infection between January 2015 and June 2019 were included. ADV infection/disease was defined as detection of ADV DNA in clinical specimens/plus symptoms. Clinical and laboratory findings, treatments, and outcomes were assessed.ResultsAdenovirus infection was diagnosed in 24 of 751 (3.2%) KT recipients. Twenty (83%) were male with a median age of 47 years (interquartile range [IQR], 36–58). Fifteen (63%) underwent deceased donor KT, and 13 (54%) received induction therapy. Twenty-one (88%) and 4 (17%) patients developed hemorrhagic cystitis and disseminated disease, respectively. There were equal distributions of early-onset (EOI) (≤3 months) and late-onset (LOI) (>3 months) infections. Patients who were diagnosed with EOI had lower median absolute lymphocyte counts compared with those with LOI (735/mm3 [IQR, 543–1123] vs 1122/mm3 [IQR, 784–1344], P = .04). All achieved resolution after reduction of their immunosuppression regimen and 13 (54%) received cidofovir therapy. Eighteen (75%) developed allograft dysfunction, of which 67% were transient. One (4%) underwent nephrectomy for allograft failure and 1 (4%) died (non-ADV–related). Patients with EOI were more likely to receive cidofovir therapy (75% vs 33%, P = .04) and develop other opportunistic infections (75% vs 8%, P < .001).ConclusionsAdenovirus infection after KT typically involves a genitourinary system and transiently impairs an allograft function. Those who developed early infection tend to have more lymphopenia, coinfection, and receive antiviral therapy.

The Efficacy and Safety of Cidofovir in Salvage Therapy for CMV Infection in the Patients with Haploid Hematopoietic Stem Cell Transplantation

Cidofovir (CDV) is a nucleotide analogue with broad antiviral activity and has been approved for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome. Data on the use of CDV for anti-CMV treatment in the patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. To evaluate the efficacy and safety of CDV in salvage treatment of CMV infection after allo-HSCT, we prospectively enrolled 18 patients with CMV infection after allo-HSCT in this study, of whom failed or intolerant to preemptive antiviral therapy. Dose of CDV as 5 mg/kg per week was used until CMV-DNA negative twice with quantification polymerase chain reaction (qPCR) detection or disease progression. All these 18 patients received haploid HSCT and suffered from a median of II (I~IV) ° acute graft versus host disease (aGVHD) before or at the same time of CMV infection. The patients showed as CMV DNAemia (n=7), CMV syndrome (n=5) and CMV disease (n=6) at a median time of 37 (range, 26 to 49) days post transplantation. Before CDV, all the patients received ganciclovir (n=9) or/and foscarnet (n=10) as pre-empty treatment for CMV infection, and 15 cases failed while 3 untolerated to the side effect. After a median of 2 (1-4) course of CDV therapy, 14 (77.8%) patients acquired clinical cure, 1 improved, and 3 (16.7%) failed, presenting a median response time of 2 courses. 11 (61.1%) patients had a 1-log decrease in CMV-DNA copy number after 1 cycle of CDV treatment, and 10 (55.6%) patients obtained virus clearance after 1 to 2 courses of treatment. With a median follow-up of 5 (1 to 12) months, 14 patients remained continuously CMV-DNA negative. During CDV treatment, 4 (22.2%) patients developed mild reversible renal damage and 5 (27.8%) experienced I~II° gastrointestinal reactions. Taking together, it could be effective and safe to use cidofovir in salvage treatment for CMV infection in the patients with allo-HSCT, including haplo-HSCT. Disclosures No relevant conflicts of interest to declare.

A RARE CASE OF DISSEMINATED ADENOVIRUS CAUSING SEPTIC SHOCK WITH MYCOPLASMA COINFECTION SUCCESSFULLY TREATED WITH CIDOFOVIR

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: We present a rare case of refractory septic shock secondary to disseminated adenovirus co-infected with Mycoplasma that was successfully treated with cidofovir. CASE PRESENTATION: A healthy 7-year-old male presented with fever and cough of 10 days. He was diagnosed with Mycoplasma pneumoniae (Mp) based on cold agglutinin screen and was given azithromycin. With no improvement in symptoms after two days, chest x-ray revealed left lower lobe pneumonia, Biofire showed adenovirus (ADV) with negative Mp, and urinalysis showed 2+ protein and 3+ blood. He was admitted to the hospital, given ceftriaxone, and started on oxygen via nasal cannula for hypoxia. He rapidly deteriorated, developed left-sided pleural effusion requiring chest tube insertion, and had more difficult oxygenation; so he was transferred to the Pediatric Intensive Care Unit. Within 24 hours, he developed respiratory failure and pressor-dependent shock requiring veno-venous extracorporeal membrane oxygenation (ECMO). Antibiotics were escalated. With progression of disease, the decision was made to initiate cidofovir therapy (5mg/kg once) that day despite known proteinuria and renal insufficiency. He developed renal failure requiring initiation of continuous renal replacement therapy (CRRT) the day after ECMO started. An Mp titer was sent showing positive IgG and elevated IgM (4933 U/mL), so azithromycin was restarted. He was also started on steroids for concern for adrenal insufficiency. Initial ADV viral load was >2million copies. After 5 days a second ADV PCR was obtained showing 942 copies, so a second cidofovir dose (1mg/kg once) was given. He was able to be decannulated on day 7 to a conventional ventilator. Two weeks later, he had an undetectable viral load and was on room air. Renal support was weaned off completely with eventual recovery of function to baseline. DISCUSSION: ADV is ubiquitous, with some genotypes causing outbreaks of life-threatening viral pneumonia even in immunocompetent adults. Reports of severe ADV pneumonia are much less common in immunocompetent children: disseminated disease occurs in less than 2% and is very rare in those older than 3 years (two published reports in adults and children above the age of 3). It is possible that Mp served as an immune modulator for ADV to cause such severe disease. CONCLUSIONS: To our knowledge, this is the first co-infection with ADV and Mp described in critically ill children; Mp has been described as coinfection for measles and pertussis. A study of the ELSO registry from 1998-2009 showed that only 38% of children on ECMO for ADV infection survived to discharge, and that survival was less common among those requiring dialysis (17%); however, this patient had good acute outcomes with the use of cidofovir. Reference #1: Munoz FM, Piedra PA, Demmler GJ. Disseminated adenovirus disease in immunocompromised and immunocompetent children. Clin Infect Dis. 1998;27(5):1194-200. Reference #2: Jeong E, Maslyanskaya S, Coupey SM. Disseminated adenovirus disease presenting as septic shock in an immunocompetent pubertal girl. Infect Dis Clin Pract 2018;26: e25–e27. Reference #3: Prodhan P, Bhutta AT, Gossett JM, Stroud MH, Rycus PT, Bratton SL, Fiser RT. Extracorporeal Membrane Oxygenation Support Among Children with Adenovirus Infection: A Review of the Extracorporeal Life Support Organization Registry ASAIO Journal 2014; 60:49–56. DISCLOSURES: No relevant relationships by Ashley Choe, source=Web Response No relevant relationships by William Dalzell, source=Web Response No relevant relationships by Kathryn Kocher, source=Web Response No relevant relationships by Bianca Rad, source=Web Response

Case presentation: persistent adenovirus B3 infections associated with bronchiolitis obliterans treated with cidofovir in a child with mosaic tetrasomy 9p

BackgroundAdenoviruses (AdV) are non-enveloped, double-stranded DNA viruses with multiple serotypes, which cause a variety of end-organ disease in both immunocompetent and immunocompromised individuals. Some adenoviruses can become latent in the mucosa-associated lymphoid tissue (e.g. adenoids and tonsils), with the potential to reactivate sporadically, leading to upper or lower respiratory tract infection and disease. Bronchiolitis Obliterans (BO) is a rare chronic lung disorder which usually follows a severe insult to the respiratory tract. In children, it is a complication of severe infections (as post-infectious BO), typically manifesting after a severe respiratory infection, in previously healthy pre-school children. Symptoms and signs of air trapping (hyperinflated chest, expiratory wheeze) with persistent oxygen requirement are characteristic. The presence of the unusual mosaic tetrasomy 9p genotype in this case, despite standard cidofovir therapy for persistent or chronic adenovirus infection, may have impacted on the child’s long-term clinical outcomes.Case presentationWe present a case of persistent AdV B3 infection in a 14-month old boy with mosaic tetrasomy 9p, which persisted for 10 weeks, resulting in radiologically-confirmed BO, requiring cidofovir to control the persistent AdV B3 infection and standard therapy with pulsed steroids. We argue that in the presence of the mosaic tetrasomy 9p, earlier antiviral therapy may have decreased the severity of BO, as this mutation is known to be associated with some degree of immune dysregulation.ConclusionsAdenovirus infections are common in children and may persist as latent infections, with subsequent reactivations during loss of immune control, related to systemic illness arising from other causes. In chronic, reactivated AdV infection with pneumonia, BO is a recognised complication. However, in this case, with the presence of the mosaic tetrasomy 9p mutation, earlier antiviral therapy may have reduced such longer term complications, due to the immune dysregulatory nature of this mutation.

Outcomes of Human Adenovirus Infection and Disease in a Retrospective Cohort of Pediatric Hematopoietic Cell Transplant Recipients.

Human adenoviruses (HAdVs) are associated with significant morbidity and death after hematopoietic cell transplantation (HCT). In this study, we sought to determine the incidence of HAdV infection among pediatric HCT recipients in the polymerase chain reaction (PCR) testing era, identify risk factors for viremia among patients undergoing HAdV surveillance, and assess the effectiveness of preemptive cidofovir. A single-center retrospective cohort of patients who underwent a transplant within a 10-year period was assembled. The incidence of and outcomes of patients with HAdV infection and disease were determined by PCR results and chart review. A Cox regression model was used for surveilled allogeneic HCT recipients to identify factors associated with viremia. We also used a discrete-time failure model with inverse probability treatment weights to assess the effectiveness of preemptive cidofovir for infection. Among 572 HCT recipients, 76 (13.3%) had ≥1 sample that was HAdV PCR positive (3.5% of autologous HCT recipients and 19.7% of allogeneic HCT recipients). Among 191 allogeneic HCT recipients under surveillance, 58 (30.4%) had HAdV detected from any source, and 50 (26.2%) specifically had viremia. The mortality rate was higher in allogeneic HCT recipients with HAdV infection versus those without infection (25.9% vs 11.3%; P = .01). Factors associated with infection included an age of 6 to 12 years, an absolute lymphocyte count of <200 cells/μL, recent prednisone exposure, and recent bacteremia. Preemptive cidofovir was not associated with a reduced risk of infection progression (odds ratio, 0.96 [95% confidence interval, 0.30-3.05]). HAdV infection is common and associated with an increased rate of death after allogeneic HCT. Using prediction models that incorporate factors associated with HAdV might help target surveillance. Preemptive cidofovir therapy was not protective in a subset of HAdV-positive patients. Larger observational or randomized investigations are necessary, because the utility of surveillance requires effective preemptive therapies.

Antiviral treatment of BK virus viremia after kidney transplantation.

The various antiviral treatment options in the management of BK virus (BKV) viremia and BKV-associated nephropathy (BKVAN) are reviewed. Review of the PubMed database from 1990 to 2016 for all English language case series, cohort studies, and randomized controlled trials detailing antiviral treatment of BKV viremia or BKVAN in kidney transplant recipients returned only 16 published reports. The majority of these reports were based on small case series or protocol-based cohort studies, with no prospective head-to-head data and only modest benefit reported for cidofovir, leflunomide, i.v. immunoglobulin (IVIG), and fluoroquinolone therapy. Given the lack of comparative data, appropriate antiviral treatment of BKV viremia should be determined based on institutional immunosuppressive protocols and posttransplantation outcomes. In appropriate patients who are not immunologically sensitized, substituting leflunomide for mycophenolate as part of immunosuppression reduction is reasonable and may result in viral clearance in up to 43% of patients at 4 weeks. In patients with persistent viremia despite immunosuppression reduction, either IVIG 2 g/kg administered over 2-5 days or cidofovir 0.5 mg/kg per week until viral clearance is achieved is generally well tolerated. Otherwise, there is insufficient evidence to recommend the use of fluoroquinolone therapy in either the treatment or prophylaxis of BKV viremia at this time. A review of the published literature revealed that certain populations of patients with BKV viremia or BKVAN can benefit from cidofovir, leflunomide, and IVIG therapy, but these data were derived from case series or protocol-driven cohort studies. Providers should treat patients on an individual basis to maximize clinical effectiveness while limiting adverse reactions.

BK Virus-Associated Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation in the Pediatric Population.

To study the incidence, risk factors, and treatment of hemorrhagic cystitis secondary to BK-virus reactivation (HC-BKV) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the pediatric population. Case-control study in which all pediatric patients (0-18 years) who underwent allo-HSCT from September 2009 to January 2014 were followed. Twenty-nine patients underwent an allo-HSCT. The median age was 9 years (range = 6 months to 15 years), 61% male. The primary diagnosis was acute lymphoblastic leukemia (72.4%). Six (20.7%) developed HC-BKV. In a multivariate analysis of risk factors, it was observed that the reactivation of BK virus was associated with age more than 10 years ( P = .098) and those with positive serology for Epstein-Barr virus ( P = .06). Five of the 6 patients with HC-BKV received cidofovir (CDV) at doses of 3 to 5 mg/kg/week. The treatment lasted a median of 3 cycles (range = 2-5). One of the patients (20%) developed nephrotoxicity. Of the 5 patients treated with CDV, 3 (60%) had a complete response, 1 (20%) partial response, and 1 (20%) no response. We conclude that HC-BKV is a frequent complication after allo-HSCT. CDV therapy can be effective but controlled clinical trials are needed.

Renal Toxicity Outcomes for Pediatric Patients Receiving Cidofovir for the Treatment of Adenovirus Infections

Introduction Conclusions Background: Adenovirus (AdV) infection is accompanied by significant morbidity and mortality in high-risk pediatric patients. Treatment options are considerably limited by toxicity. Nephrotoxicity has been associated with cidofovir therapy, although most pediatric studies report little or no morbidity with its use. Pharmacokinetic (PK) data for children is limited; a pediatric PK study determined that cidofovir half-life was significantly longer in children than adults (Brown, 2015).

Cidofovir in pediatric solid organ transplant recipients: University of Nebraska experience.

Clinical experience with cidofovir in pediatric solid organ transplantation is limited. We assessed the effect of cidofovir use on renal function in pediatric solid organ transplant recipients. Wilcoxon signed-rank tests were used to determine if changes in renal function were significant, Wilcoxon rank-sum tests to test the association between changes in glomerular filtration rate and potential confounding factors, and MacNemar tests to compare the proportions of patients at different time points. We included 25 patients with a mean age of 4.2 years (SD 4.6). More patients were receiving renal replacement therapy while being treated with cidofovir compared with baseline (24% vs. 4%; P = 0.03). For patients not receiving renal replacement therapy, there was no evidence of a significant median change in glomerular filtration rate from baseline to 1 month after cidofovir treatment (P = 0.32) or to the end of cidofovir treatment (P = 0.23) or in creatinine from baseline to the end of cidofovir therapy (P = 0.2). There was a marginal decreased median change in creatinine from baseline to 1 month after cidofovir treatment (P = 0.06). Fewer patients had proteinuria (72.2% vs. 27.8%; P = 0.02) and hematuria (22.2% vs. 0%) after cidofovir treatment. In our pediatric transplant cohort, cidofovir did not significantly change renal function reflected by creatinine, glomerular filtration rate, hematuria or proteinuria, but a significant number of patients required renal replacement therapy because of fluid overload.

The broad-spectrum anti-DNA virus agent cidofovir inhibits lung metastasis of virus-independent, FGF2-driven tumors.

The FDA-approved anti-DNA virus agent cidofovir (CDV) is being evaluated in phase II/III clinical trials for the treatment of human papillomavirus (HPV)-associated tumors. However, previous observations had shown that CDV also inhibits the growth of vascular tumors induced by fibroblast growth factor-2 (FGF2)-transformed FGF2-T-MAE cells. Here, we demonstrate that CDV inhibits metastasis induced by FGF2-driven, virus-independent tumor cells. Pre-treatment of luciferase-expressing FGF2-T-MAE cells with CDV reduced single cell survival and anchorage-independent growth in vitro and lung metastasis formation upon intravenous inoculation into SCID mice. This occurred in the absence of any effect on homing of FGF2-T-MAE cells to the lungs and on the growth of subconfluent cell cultures or subcutaneous tumors in mice. Accordingly, CDV protected against lung metastasis when given systemically after tumor cell injection. Lung metastases in CDV-treated mice showed reduced Ki67 expression and increased nuclear accumulation of p53, indicating that CDV inhibits metastasis by affecting single cell survival properties. The anti-metastatic potential of CDV was confirmed on B16-F10 melanoma cells, both in zebrafish embryos and mice. These findings suggest that CDV may have therapeutic potential as an anti-metastatic agent and warrants further study to select those tumor types that are most likely to benefit from CDV therapy.

The Effectiveness Of Cidofovir In Disseminated Adenovirus Infections After Pediatric HSCT Is Closely Related To Lymphocyte Reconstitution

Human Adenovirus (HAdV) reactivation is a frequent and potentially fatal complication in pediatric allogeneic stem cell transplantation (HSCT) recipients, especially after in vivo T-cell depletion. Patients with HAdV reactivations are generally treated with the antiviral agent Cidofovir (CDV), a monophosphate nucleotide analogue. Studies reporting effectiveness of CDV therapy are mostly incomplete due to lack of data on the immune status of the patients. Here, we report the relationship between the effectiveness of CDV therapy and lymphocyte reconstitution as well as the acute and chronic nephrotoxicity of CDV in the setting of pediatric .infections after pediatric HSCT.Between 2003 and 2012, 321 children received 363 allogeneic transplantations in our pediatric HSCT center. HAdV reactivations were monitored by weekly plasma HAdV DNA RQ-PCR. Disseminated infections, defined as two consecutive PCR values above 103 (3 log ) copies / mL occurred in 40 patients (12 %). 30 patients were treated with CDV for infections with an HAdV load ≥ 3 log at start of therapy. In 27 patients, sufficient data were available to evaluate the effectiveness of CDV. Cidofovir was administered IV 3x / week at 1 mg / kg. Prehydration and Probenecid were used to reduce the risk of nephrotoxicity. Patient were median 4.5 (0.5 - 18) years of age and 26 of 27 patients received in vivo T-cell depletion. CDV therapy was initiated median 28 (1 - 121) days after HSCT while the median treatment duration was 15 (1 - 99) days. At start of CDV treatment, the HAdV load was median 4.2 log (range 3.1 log - 6.5 log) copies / mL.Response was evaluated after 14 days of CDV therapy. A ≥ 10x (1 log) reduction of HAdV load was measured in 10 of 27 evaluable patients (37%) while 13 patients (48%) showed a stabilization of HAdV load. CDV treatment failed in 4 patients (15 %), as define by a 1 log increase of HAdV load despite uninterrupted CDV therapy. In 23 patients with a reduction or stabilization of the HAdV load, lymphocyte numbers increased strongly in the two weeks after initiation of CDV treatment (median 130 to 608 lymphocytes / µL, p < 0.0001, Wilcoxon signed-rank test). This increase was caused by reconstitution of NK cells (n = 5), T-cells (n = 4) or both (n = 12). In only 2 patients with a stabilization of HAdV load, no concomitant reconstitution of NK or T-cells was observed.Ultimately, 17 patients (63 %) cleared the virus 5 - 89 (median 33) days after the initiation of CDV therapy. The moment of HAdV clearance was strongly correlated to the first day the T-lymphocytes reached 50 cells/ µl (R2 = 0.79, p < 0.0001, linear regression analysis). 7 patients died of progressive HAdV viremia with multi-organ failure (MOF) at 20 - 154 (median 51) days after initiation of CDV therapy. Three patients were not evaluable as they died of another cause (n=2) or were lost to follow up (n=1) without clearance of the virus.For the analysis of CDV nephrotoxicity, 3 patients with HAdV related MOF during CDV therapy were excluded, leaving 24 patients. In 4 patients (17%), CDV therapy had to be discontinued because of acute glomerular failure, which invariably occurred within the first 2 weeks of treatment. Tubular kidney failure, defined by the need for suppletion of phosphate, magnesium or bicarbonate, was observed in 17 of 24 patients (71%). Kidney failure was transient in the majority of patients. After 1 year, 1 of 12 survivors (8 %) had chronic glomerular and tubular kidney failure that could not be explained by nephrotoxic co-medication. In 9 additional HSCT recipients who received > 7 days of CDV therapy for non-disseminated HAdV infections, 1 of 8 surviving patients (13 %) had chronic kidney failure that was unlikely to be caused by other nephrotoxic medication.In conclusion, a reduction of HAdV load in the first 2 weeks of therapy was always accompanied by lymphocyte recovery while Cidofovir could not prevent further dissemination in 4 of 27 patients. In most patients with a stabilization of the viremia, this could be attributed to both CDV as well as T- or NK-cell reconstitution whereas in only 2 patients (7%), the HAdV load stabilized in the absence of lymphocyte recovery. These data suggest that CDV possibly plays a role in the stabilization of HAdV viremia in the time pending T-cell recovery. In view of the considerable toxicity profile, a multicenter randomized clinical trial is warranted to establish efficacy of CDV treatment for disseminated HAdV infections after pediatric HSCT.▪ Disclosures:Off Label Use: The antiviral agent Cidofovir (CDV), a monophosphate nucleotide analogue, is widely used off-label for the treatment of disseminated Human Adenovirus infections after Pediatric Hematopoietic Stem Cell Tansplantation.

Treatment of BK virus‐associated hemorrhagic cystitis in pediatric hematopoietic stem cell transplant recipients with cidofovir: a single‐center experience

BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is a severe complication after hematopoietic stem cell transplantation (HSCT). Cidofovir (CDV) has emerged as an effective agent for the treatment of BKV nephropathy, but its use for BKV-HC in pediatric HSCT recipients has not yet been established as a standard therapy. We retrospectively investigated the efficacy and safety of CDV therapy for patients with BKV-HC at a single institution and analyzed the clinical management outcomes. From April 2009 to July 2011, 12 patients developed BKV-HC at a median of 37 days after transplant (range 15-59 days). The cumulative incidence was 9% and the median peak of the urine BKV load was 2.5 × 10(10) copies/mL (range 1.4 × 10(9) -1.2 × 10(11) copies/mL). Eleven patients received intravenous CDV (5 mg/kg/dose, with probenecid), whereas 1 patient received CDV (5 mg/kg/dose, without probenecid) intravesically. The median duration of therapy was 25 days (range 9-73 days), and a median of 2 doses was given (range 1-4). A reduction of ≥ 1 log in the BKV load was found in 11 patients, while 1 patient did not have any significant change in BKV load. Clinical improvement was observed in all cases, and no HC-related death was observed. CDV-related toxicity occurred in 1 patient (8%) and spontaneously resolved. CDV appears to be an effective and safe treatment for BKV-HC in pediatric HSCT recipients, but prospective trials are warranted to support its use.

Severe Necrotizing Adenovirus Tubulointerstitial Nephritis in a Kidney Transplant Recipient

Adenoviruses (AdV) are emerging pathogens with a prevalence of 11% viruria and 6.5% viremia in kidney transplant recipients. Although AdV infection is common, interstitial nephritis (ADVIN) is rare with only 13 biopsy proven cases reported in the literature. We report a case of severe ADVIN with characteristic histological features that includes severe necrotizing granulomatous lesion with widespread tubular basement membrane rupture and hyperchromatic smudgy intranuclear inclusions in the tubular epithelial cells. The patient was asymptomatic at presentation, and the high AdV viral load (quantitative PCR>2,000,000 copies/mL in the urine and 646,642 copies/mL in the serum) confirmed the diagnosis. The patient showed excellent response to a combination of immunosuppression reduction, intravenous cidofovir, and immunoglobulin therapy resulting in complete resolution of infection and recovery of allograft function. Awareness of characteristic biopsy findings may help to clinch the diagnosis early which is essential since the disseminated infection is associated with high mortality of 18% in kidney transplant recipients. Cidofovir is considered the agent of choice for AdV infection in immunocompromised despite lack of randomized trials, and the addition of intravenous immunoglobulin may aid in resolution of infection while help prevention of rejection.

Effect of Low Dose Cidofovir in Kidney Transplant Recipients with Polyomavirus Associated Nephropathy

Background: Polyomavirus associated nephropathy (PVAN) is an important cause of graft dysfunction and graft failure in current era of immunosuppressant. First treatment is early reduction of immunosuppressant, but the rate of graft failure is still high. And there is no consensus on its management. Cidofovir, antiviral drug for cytomegalovirus, is thought to have therapeutic effect for polyomavirus, but the benefits are still controversial. Patients and methods: We treated Biopsy proven PVAN patients between 2008˜2010 in single center. All patients were treated with a reduction of their original immunosuppressive medications. 15 patients agreed to receive low-dose cidofovir (0.25 mg/kg) every 2 weeks for a total of eight doses. Result: They received mean 7.5 times (3˜14) of cidofovir with mean dose of 2.9 mg/kg (1.0˜6.5mg/kg). Mean serum creatinine level increased from 2.4mg/dl, at the start of cidofovir to 2.6 mg/dl, at the end of cidofovir. Mean BKV blood PCR reduced from 6.5 logs to 5.9 logs. There was no adverse effect of cidofovir. After 6 month of treatment, renal function was improved in 7 patients compared to at the time of initial cidofovir use. During 2.7 years of follow up there was no rejection episode but one graft failure due to chronic allograft nephropathy. Dose of cidofovir, time interval between diagnosis of PVAN and cidofovir treatment, initial BKV blood PCR level, and initial creatinine were not associated with clinical outcome. Conclusion: Adverse effect of low dose cidofovir is uncommon and low dose cidofovir therapy in PVAN patients seems to be beneficial in addition to reduction of immunosuppressant. But this small series of cidofovir use does did not prove that cidofovir in addition to immunosuppressant reduction is better than immunosuppressant reduction alone. These findings warrant a randomized controlled prospective study in order to asses the clinical value of adjuvant low-dose cidofovir.