Cidofovir plasma assays after local injection in respiratory papillomatosis

OBJECTIVE: To assess cidofovir plasma concentration after intralesional airway administration for recurrent respiratory papillomatosis. DESIGN: Prospective study. SETTING: Tertiary care teaching hospital. PATIENTS AND METHOD: The study comprised 21 patients (10 children and 11 adults). Plasma samples were collected at 10 and 45 minutes (T10, T45) or at 10 and 60 minutes (T10, T60) after injection. The measurements of cidofovir were performed using a high-performance liquid chromatographic method. RESULTS: Plasma samples were collected at T10 and T45 on 19 occasions from the children and on 17 from the adults. A linear relationship was found between plasma concentration and dose in children (mean dose 1.2 mg/kg; mean cidofovir plasma levels 0.91 and 0.81 microg/mL) but not in adults (mean dose 0.2 mg/kg; mean plasma levels 0.21 and 0.31 microg/mL). The same relationships were found between dose and area under the concentration/time curve (AUC). Four plasma samples were taken in children at T10 and T60: mean dose 1.2 mg/kg and mean plasma concentrations 1.11 and 1.24 microg/mL. Maximum plasma concentration averaged 34% (SD 11%) in children and 62% (SD 33%) in adults, with equivalent plasma level after intravenous infusion of the same dose. CONCLUSIONS: The cidofovir plasma levels were below those leading to toxicity. The levels and the AUC were dose dependent in children but not in adults. Diffusion from the injected site was greatest in a few adults and unpredictable. Because of the great individual variation in diffusion in adults, cidofovir should be used at less than the recommended intravenous dose to prevent any risk of systemic toxicity.     

Intermediate dose cidofovir does not cause additive nephrotoxicity in BK virus allograft nephropathy

BKVAN has emerged as a major morbidity in kidney transplant recipients. Among treatment options is cidofovir, which can be nephrotoxic. We previously reported that intermediate dose cidofovir could be used without significant nephrotoxicity. We present extended results of the same treatment protocol in a larger cohort and with longer follow up. Diagnosis of BKVAN was based on detection of BK viral DNA from plasma and renal allograft biopsy tissue. All patients received cidofovir (0.25-1 mg/kg/dose) every 2-3 wk. Total number of cidofovir doses ranged from 1 to 18 (mean 8). This report includes eight patients, aged 5-21 yr, treated with intermediate dose cidofovir. Median follow-up was 11 months (range 4-32). Mean fall in reciprocal of serum creatinine (1/sCr) from baseline at BKVAN diagnosis was 64% (range 28-120%). A time-series plot of plasma BK virus PCR and 1/sCr showed marked reduction in viral loads without significant deterioration in 1/sCr from the initial value at BKVAN diagnosis. In this larger series with extended follow up, intermediate dose cidofovir without probenecid for the treatment of BKVAN continues to show stabilization of renal function without progression to renal failure.     

Intermediate-dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy

BK virus allograft nephropathy (BKVAN) is a rising complication in kidney transplant recipients. Reducing immunosuppression has been the initial form of therapy in most cases, but is not always associated with improvement in graft function. Anti-viral therapy with low-dose cidofovir (0.25-0.42 mg/kg/dose) has been used successfully in some patients, but dose-related nephrotoxicity has limited its use. We present our experience with 3 kidney transplant recipients diagnosed with BKVAN who received intermediate-dose cidofovir (0.75-1.0 mg/kg/dose) without probenecid, and without concomitant nephrotoxicity. Three female patients, ages 8, 19 and 20 yr, presented with elevated serum creatinine (SCr) values, BK virus stain positive on renal biopsy and high plasma BK viral loads. As a result of viral loads being >2 million copies/ml in two patients and a lack of response to reduction in immunosuppression in the third, we initiated therapy with low-dose cidofovir. Because of persistent positive BK stain and positive plasma viral load, we then administered intermediate-dose cidofovir, without probenecid, for several subsequent doses (seven to 15 infusions till date). All patients tolerated the intermediate-dose cidofovir with no significant rise in SCr during the course of the infusions. The most recent SCr values in all three patients were improved from those at the initial diagnosis of BKVAN. All three patients showed a marked drop in BK viral loads when on intermediate-dose cidofovir, with complete clearing of viremia in two patients. In our experience, intermediate-dose cidofovir without probenecid, used judiciously, is not associated with additional nephrotoxicity and may provide an additional alternative for treatment.     

Adenovirus infection and treatment with cidofovir in children after liver transplantation

Abstract:  In a retrospective study, serum samples from 21 pediatric liver transplant recipients were analysed by quantitative real-time PCR for ADV infection up to 24 wk after Tx. ADV DNA was detected in serum of eight children after Tx, one of whom developed life-threatening fulminant hepatitis and sepsis. None of these children were symptomatic at the time of first detection of ADV DNA in serum after Tx. Seven children with positive ADV PCR had low adenoviral loads, showed no increase in viral load and remained clinically asymptomatic in the follow-up period of 24 wk. After 10 wk under immunosuppression one child presented clinically with adenoviral sepsis and severe necrotizing hepatitis. This patient revealed a dramatic increase of ADV from baseline titers up to 1.3 × 10⁹ copies/mL serum within 10 wk after Tx. ADV was also detected in a liver biopsy of this child at 1.2 × 10⁴ copies/cell and typed by sequence analysis as human ADV species C, type 6, a rarely detected ADV type and first described in a liver transplant patient. Immunosuppression was reduced in this patient immediately and the antiviral drug cidofovir administered intravenously followed by viral suppression and clinical improvement of the child.     

广谱抗病毒药物西多福韦的合成

目的优化西多福韦的合成工艺。方法利用三苯甲基保护的（R）-缩水甘油经碳酸铯催化与胞嘧啶缩合,二甲基乙缩醛保护氨基后,在NaH作用下引入甲基磷酸二乙酯,再脱去不同的保护基得到西多福韦。结果西多福韦结构经光谱确定;纯度〉99.5%,总收率为23%。结论该合成路线短,条件温和,纯化方便,试剂成本低,适合规模化合成制备。     

Drug-induced Uveitis in HIV Patients with Ocular Opportunistic Infections

ABSTRACT

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.     

KSHV Targeted Therapy: An Update on Inhibitors of Viral Lytic Replication

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Since the discovery of KSHV 20 years ago, there is still no standard treatment and the management of virus-associated malignancies remains toxic and incompletely efficacious. As the majority of tumor cells are latently infected with KSHV, currently marketed antivirals that target the virus lytic cycle have shown inconsistent results in clinic. Nevertheless, lytic replication plays a major role in disease progression and virus dissemination. Case reports and retrospective studies have pointed out the benefit of antiviral therapy in the treatment and prevention of KSHV-associated diseases. As a consequence, potent and selective antivirals are needed. This review focuses on the anti-KSHV activity, mode of action and current status of antiviral drugs targeting KSHV lytic cycle. Among these drugs, different subclasses of viral DNA polymerase inhibitors and compounds that do not target the viral DNA polymerase are being discussed. We also cover molecules that target cellular kinases, as well as the potential of new drug targets and animal models for antiviral testing.     

BK polyomavirus encephalitis in a patient with thrombotic microangiopathy after an allogeneic hematopoietic stem cell transplant

To date, only one case of BK polyomavirus (BKPyV) encephalitis combined with transplant‐associated thrombotic microangiopathy has been reported in an hematopoietic stem cell transplantation (HCT) recipient. We report the case of an HCT recipient who developed thrombotic microangiopathy and subsequent BKPyV encephalitis. She died despite treatment with cidofovir, ciprofloxacin, and intravenous immunoglobulin without improvement in mental status. Early suspicion of BKPyV encephalitis in an HCT recipient presenting with altered mental status and hemorrhagic cystitis is important.