Cidofovir inhibits growth of B16 melanoma cells in vivo

BACKGROUND: Cidofovir [(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine] is a commercially available nucleotide analogue that has antiviral activity against a broad range of DNA viruses and is effective against human cytomegalovirus infection. OBJECTIVES: We aimed to study the effect of cidofovir on growth of the highly aggressive melanoma tumour arising from mouse melanoma B16 cells grafted subcutaneously in C57B16/J mice. METHODS: Mice were treated daily with systemic cidofovir at several doses. In treated and control groups, tumour growth was measured using a calliper, and histological studies were performed. RESULTS: In untreated mice, massive invasive melanoma tumours were observed on day 5 after tumour cell grafting. Cidofovir treatment gave a dose-dependent reduction in tumour size. Tumour growth was inhibited by 62% at a dose of 37.5 mg kg(-1) three times weekly, as compared with control mice treated with saline alone. At 67 mg kg(-1) three times weekly, tumour growth was inhibited by 90%. Increasing the cidofovir dose to 50 or 100 mg kg(-1) daily resulted in a gradual increase in the antitumoral effect of the compound. In one experiment, cidofovir was administered at 100 mg kg(-1) five times weekly from the eighth day after the injection of tumour cells, when the tumour already had a volume of approximately 100 mm(3). In the treatment group, on the 14th day the tumour volume was approximately 200 mm(3), while in the control group it had increased to 750 mm(3). CONCLUSIONS: Although the mechanism is unknown, an antitumoral or antiangiogenic effect may be the reason for the activity of cidofovir in this model. In view of our findings, use of cidofovir should be further explored in the treatment of neoplastic diseases.     

Successful use of intralesional and intravenous cidofovir in association with indole-3-carbinol in an 8-year-old girl with pulmonary papillomatosis

We report the history of an 8-year-old girl who was treated for suspected lung lesions of respiratory papillomatosis with Indole-3-Carbinol, local and intravenous injections of Cidofovir for 27 months. This is the first report where a complete cure of the lung lesions occurred in a child, and was sustained for at least 24 months.     

Invasive adenoviral infection in a recipient of unrelated bone marrow transplantation: Problems with diagnostic PCR

A hematopoietic stem cell transplantation (SCT) recipient developed severe diarrhea and fever. A rapid test for the presence of adenovirus (AdV)-specific antigen in the patient's stools was positive; however, AdV genome was not detected by conventional or real-time polymerase chain reaction (PCR). AdV was confirmed by specific PCR for AdV serotype 7 and by an AdV hexon/fiber gene DNA sequence homology search of the PCR product. We suspect that conventional/real-time PCR failed to detect AdV due to nine silent single base substitutions in the extracted AdV genome. Treatment with 1 mg/kg cidofovir (CDV) intravenously three times a week was effective.     

西多福韦临床研究进展

西多福韦(抗病毒药)属无环核酸类药物,有广谱抗DNA病毒活性。美国FDA已批准其临床用于治疗艾滋病(AIDS)患者的巨细胞病毒视网膜炎。近年来,用西多福韦试治疗多种DNA病毒感染、病毒性皮肤病及肿瘤均取得了不同程度的疗效,本文综述其最新进展。     

Adenovirus Disease after Kidney Transplantation: Course of Infection and Outcome in Relation to Blood Viral Load and Immune Recovery

Information on the clinical spectrum and management of adenovirus infection after kidney transplantation is limited. From April 2007 to April 2010, 17 kidney transplant recipients were diagnosed with adenovirus disease. The median time to infection was 5 (range, 2–300) weeks after transplantation. Of the 17 patients, 13 (76.5%) presented early, within 3 months posttransplant, and four (23.5%) presented late, more than 3 months after transplant. Besides urinary tract, involvement of other organs was common (63.6%) among patients with adenovirus viremia. Despite reduction of immunosuppression, six patients subsequently had a rise in the level of blood viral load, mostly within a week after diagnosis. However, only three (27.3%) patients with early infection developed disease progression. Compared to the late infection group, patients with early infection had significantly lower absolute lymphocyte counts at week 1 (p = 0.01) and 3 (p = 0.002) after diagnosis. Four patients received intravenous cidofovir. At 6‐month follow‐up, 10 (90.9%) patients had reversible graft dysfunction. Only one (5.7%) died from bacterial sepsis. Adenovirus disease is a significant complication following kidney transplantation. Early case recognition with reduction of immunosuppression is critical. Serial blood adenovirus viral loads and assessment of lymphocyte recovery are also useful in monitoring the course of infection.     

Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir

BACKGROUND: Adenovirus (ADV) infection occurs in 5-21% of allogeneic hematopoietic stem cell transplants (HSCT). Symptomatic enteritis and hemorrhagic cystitis may be encountered but are seldom fatal. In contrast, mortality rates of up to 75% are reported for adenoviral pneumonia or hepatitis. Cidofovir is currently being increasingly used for treatment of adenoviral infections after HSCT. The efficacy of cidofovir in patients with invasive adenoviral infection is not established. FINDINGS: We reviewed 687 adult and pediatric patients who received allogeneic HSCT at our institution from 1998 through June 2005. ADV was isolated from 64 (9.3%) patients. Eleven patients received cidofovir for invasive disease occurring at median 39 days (range 3-145) post HSCT. The median age was 40 (range 6-61) years. Seventy-three percent received a T-cell-depleted graft and 18% had grade 3-4 graft-versus-host disease (GVHD) of the gut. Three out of 3 (100%) patients with adenoviral pneumonia died. One patient with hepatitis, cholecysitis, and viremia cleared the infection after 3 months. Two out of 7 (28.6%) patients with hemorrhagic colitis or cystitis died of ADV (1 with extensive GVHD). CONCLUSION: Mortality rates of ADV pneumonitis after allogeneic HSCT remain high in the era of cidofovir. Clinical trials are needed to evaluate management strategies for this life-threatening infection.     

Adenovirus causing fever,upper respiratory infection,and allograft nephritis complicated by persistent asymptomatic viremia

A 20‐year‐old woman, with renal transplant complicated by recurrence of focal segmental glomerulosclerosis and post‐transplant lymphoproliferative disorder, presented nearly 2 years after transplantation with fever, conjunctivitis, and sinus congestion. She was found to have severe adenovirus (ADV)‐induced granulomatous interstitial nephritis, confirmed by immunohistochemical staining for ADV in the renal biopsy, without urinary symptoms, hematuria, or laboratory evidence of a change in allograft function. Fever, upper respiratory tract symptoms, and evidence of adenoviral infection in the allograft resolved with decreased immunosuppression and treatment with cidofovir and intravenous immunoglobulin. Creatinine rose during treatment and remained elevated, possibly related to cidofovir nephrotoxicity. Despite therapy and continued reduction in immunosuppression, asymptomatic low‐level viremia persisted for a year. In renal transplant patients with ADV infection, allograft involvement should be highly suspected even without overt urinary symptoms or laboratory evidence of allograft dysfunction. Demonstration of allograft involvement may prompt alternative management that could limit continued allograft infection. No clear recommendations exist for management of asymptomatic ADV viremia in solid organ transplant patients.     

Fatal BK virus pneumonia following stem cell transplantation

We report the case of a 39‐year‐old male patient who died of severe BK virus (BKV) pneumonia 168 days after hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia. After suffering from BKV‐associated late‐onset hemorrhagic cystitis (HC) with long‐term sustained BKV viremia, he died of rapidly progressive pneumonia. On autopsy, numerous viral intranuclear inclusions were seen in his lungs and bladder. An immunohistochemical examination of his lungs was positive for simian virus 40. Based on these pathological results and the high sustained BKV viral load in his blood, we reached a diagnosis of BKV pneumonia. Viral infection can occasionally become life threatening among HSCT recipients. It is widely known that BKV can cause late‐onset HC, but BKV‐associated pneumonia is rare. Because of its rapid progression and poor prognosis, it is difficult to make an antemortem diagnosis of BKV pneumonia. A treatment strategy for BKV pneumonia also needs to be formulated. Similar to other viral pathogens, BKV can cause pneumonia and the clinician should therefore be aware of it in immunocompromised patients.     

Treatment of Refractory BK Virus-Associated Nephropathy With Cidofovir

BK virus-associated nephropathy (BKVN) has become recognized as an important cause of allograft dysfunction in renal transplant recipients and despite reduction in immunosuppression, 30-40% of recipients ultimately progress to allograft loss. Cidofovir is an antiviral agent that demonstrates in vitro activity against murine polyomavirus and has been proposed for treatment of BKVN in renal allograft recipients. We describe the clinical course, renal function, serial renal histology and urine and blood viral load measurements in two consecutive patients with refractory BKVN who were treated with low-dose cidofovir (0.25 mg/kg IV). In each case, renal dysfunction and BK viral load progressed despite reduced immunosuppression, and persistent BK virus infection was documented in serial renal allograft biopsy specimens. Administration of low-dose cidofovir was associated with clearance of BK virus DNA from blood and allograft, and stabilization of renal function in both patients, without significant toxicity. These preliminary data suggest that low-dose cidofovir may be tolerated, even among renal transplant recipients with significant renal dysfunction due to BKVN. Prospective, controlled trials are warranted to further define the optimal dose, toxicity and potential role of cidofovir in renal transplant recipients with BK virus nephropathy.