First Report of Successful Treatment of Multidrug‐Resistant Cytomegalovirus Disease with the Novel Anti‐CMV Compound AIC246

We report the first case of cytomegalovirus (CMV) disease treated with AIC246, a novel anti‐CMV compound which targets the viral terminase complex and remains active against virus resistant to DNA polymerase inhibitors. A lung transplant recipient developed refractory multidrug‐resistant CMV disease involving the lungs, gastrointestinal tract and retina. His disease progressed despite treatment with all DNA polymerase inhibitors; multiple agents reported to have activity against CMV in case series, and reduction in his immunosuppressive medications. AIC246 which is in clinical development was obtained for emergency use, and combined with additional reduction in immunosuppression resulted in rapid clinical, virological and radiological resolution of disease. The patient has remained free of CMV disease or viremia off treatment for greater than 3 months. In summary AIC246, while still in development, may be a promising alternative to current therapies.     

麻疹减毒活疫苗治疗上皮型单纯疱疹病毒性角膜炎临床观察

目的探讨麻疹减毒活疫苗治疗上皮型单纯疱疹病毒性角膜炎(HSK)的临床效果。方法选取在钟祥市人民医院眼科门诊确诊的60例(60眼)上皮型HSK患者,随机分为对照组和试验组,每组30例。对照组给予更昔洛韦滴眼液滴眼,每日8次;试验组球结膜下注射麻疹减毒活疫苗,隔日1次,每次0.5 mL,联合更昔洛韦滴眼液滴眼,每日8次,治疗3周。观察治疗后1、2、3周的治疗效果,随访2 a,观察其复发率。结果对照组在治疗后第1、2、3周的症状与体征评分分别为2.533±0.507、2.133±0.730、1.433±0.728,试验组分别为2.200±0.252、1.800±0.761、1.067±0.254,2组各相应时间点评分比较差异均有统计学意义(P<0.05);治疗后第1、2、3周2组间各时间对应点角膜知觉情况比较差异有统计学意义(P<0.05)。对照组在治疗后第2、3周眼部炎症反应的治愈率分别为13.33%(4/30)、26.67%(8/30),试验组分别为33.33%(10/30)、66.67%(20/30),2组比较差异有统计学意义(P<0.05)。随访2 a,对照组复发率为26.67%,试验组为6.67%,2组比较差异有统计学意义(P<0.05))。2组患者均未出现明显不良反应。结论应用更昔洛韦滴眼液联合麻疹减毒活疫苗球结膜下注射治疗上皮型HSK具有治愈率高、不良反应少、复发率低等优点。     

Ganciclovir‐resistant post‐transplant cytomegalovirus infection due to combined deletion mutation at codons 595‐596 of the UL97 gene

The development of antiviral‐resistant cytomegalovirus (CMV) infection complicates the management of transplant recipients. We describe the case of a 65‐year‐old male who developed CMV disease on valganciclovir prophylaxis (donor CMV IgG positive, recipient CMV IgG indeterminate) 30 days after combined liver–kidney transplantation for alcoholic cirrhosis and hepato‐renal syndrome. After an initial complete response to treatment dose oral valganciclovir, he developed recurrent CMV viraemia. Resistance testing revealed a UL97 mutation with in‐frame deletions of codons 595‐596. He was treated successfully with foscarnet and reduction in immunosuppression. This mutation has not been described previously and was suspected to confer ganciclovir resistance. Ganciclovir resistance occurs most commonly due to mutations in the UL97 or UL54 genes, which encode a protein kinase and a DNA polymerase, respectively. The UL97‐encoded protein kinase phosphorylates ganciclovir to ganciclovir triphosphate, which competitively inhibits viral replication. Mutations in the UL97 gene are typically point mutations or deletions. We describe a new mutation, del595‐596 in the CMV UL97 gene, occurring in the context of clinical treatment failure with standard and double‐dose ganciclovir, and successful virological control achieved with foscarnet. This mutation is likely to result in ganciclovir resistance, although recombinant phenotyping is required for confirmation.     

Long-Term Preservation of Vision in Progressive Outer Retinal Necrosis Treated with Combination Antiviral Drugs and Highly Active Antiretroviral Therapy

Purpose: To report the successful long-term treatment of varicella zoster virus-associated progressive outer retinal necrosis (VZV-PORN) with aggressive antiviral combination drugs along with highly active antiretroviral therapy (HAART). Design: Interventional case report. Methods: Combined treatment of progressive outer retinal necrosis in a university-based tertiary eye hospital with ganciclovir implant, intravenous acyclovir (10 mg/kg every 8 h), intravitreal foscarnet (2.4 mg), and HAART. Results: Successful treatment of progressive outer retinal necrosis with disease remission and preservation of 20/20 visual acuity out to 1 year. Conclusions: Combination antiviral therapy and HAART may improve long-term visual outcomes for VZV-PORN.     

Cytomegalovirus in transplantation - challenging the status quo

BACKGROUND: Cytomegalovirus (CMV) infection of solid organ transplant (SOT) recipients causes both 'direct' and 'indirect' effects including allograft rejection, decreased graft and patient survival, and predisposition to opportunistic infections and malignancies. Options for CMV prevention include pre-emptive therapy, whereby anti-CMV agents are administered based on sensitive viral assays, or universal prophylaxis of all at-risk patients. Each approach has advantages and disadvantages in terms of efficacy, costs, and side effects. Standards of care for prophylaxis have not been established. METHODS: A committee of international experts was convened to review the available data regarding CMV prophylaxis and to compare preventative strategies for CMV after transplantation from seropositive donors or in seropositive recipients. RESULTS: Pre-emptive therapy requires frequent monitoring with subsequent treatment of disease and associated costs, while universal prophylaxis results in greater exposure to potential toxicities and costs of drugs. The advantages of prophylaxis include suppressing asymptomatic viremia and prevention of both direct and indirect effects of CMV infection. Meta analyses reveal decreased in mortality for patients receiving CMV prophylaxis. Costs associated with prophylaxis are less than for routine monitoring and pre-emptive therapy. The optimal duration of antiviral prophylaxis remains undefined. Extended prophylaxis may improve clinical outcomes in the highest-risk patient populations including donor-seropositive/recipient-seronegative renal transplants and in CMV-infected lung and heart transplantation. CONCLUSIONS: Prophylaxis is beneficial in preventing direct and indirect effects of CMV infection in transplant recipients, affecting both allograft and patient survival. More studies are necessary to define optimal prophylaxis regimens.     

高效液相色谱法-二极管阵列检测器考察炎琥宁在更昔洛韦葡萄糖注射液中的配伍稳定性

目的考察室温（20±1）℃下,注射用炎琥宁与更昔洛韦葡萄糖注射液配伍的稳定性,为临床合理用药提供依据。方法采用反相高效液相色谱法-二极管阵列检测器同时测定炎琥宁与更昔洛韦配伍后0-6 h内的含量变化,并观察配伍液的外观及pH值。结果6 h内混合液外观、pH及含量均无明显变化。结论在室温（20±1）℃条件下,注射用炎琥宁与更昔洛韦葡萄糖注射液6 h内可以配伍使用。     

Oral valganciclovir: a new option for treatment of cytomegalovirus infection and disease in immunocompromised hosts

Immunocompromised hosts are at increased risk of cytomegalovirus (CMV) infection and serious CMV disease. CMV infection is an important cause of morbidity among patients infected with HIV and after solid organ transplantation (SOT) and may cause life-threatening disease in allogeneic stem cell transplant (SCT) recipients. The introduction into clinical use of potent antiviral compounds and of rapid detection assays for CMV during the past two decades has allowed development of strategies for the prevention and treatment of disease caused by CMV in these groups of immunocompromised patients. At present, the antiviral drugs ganciclovir, foscarnet and cidofovir are commonly used in the treatment of CMV infection and disease. However, these agents have a poor oral bioavailability and, for systemic use, require iv. administration for most indications. Valganciclovir is an oral prodrug of ganciclovir, with a 10-fold greater bioavailability than oral ganciclovir. Studies of the pharmacokinetics of valganciclovir among HIV-infected CMV-seropositive patients and liver transplant recipients suggest that this oral compound has the potential to replace both oral and iv. ganciclovir in many situations if it is shown to be as efficacious and safe as those ganciclovir formulations in immunodeficient patients. In the first part of this review, currently established approaches to the management of CMV infection and disease in SCT and SOT recipients and HIV-infected patients are discussed to highlight possible indications for future valganciclovir use; in the second part, data from human studies of valganciclovir are presented.     

更昔洛韦治疗婴儿巨细胞病毒肝炎临床疗效观察

目的评价更昔洛韦治疗婴儿巨细胞病毒肝炎(CMV肝炎)的疗效及毒副作用。方法将32例确诊为巨细胞病毒肝炎患儿(简称治疗组)予以更昔洛韦治疗,同时辅以护肝、退黄、补充维生素等综合治疗;另设2000年以前确认的CMV肝炎30例为对照组,仅予传统综合治疗。结果更昔洛韦治疗可使CMVIgM的阴转率达62.5%,在降低转氨酶、肝脏回缩、黄疸消退等方面明显优于对照组,差异有显著性(P<0.05);治疗组中15.6%出现白细胞降低,6.3%血小板下降,无其他毒副作用。结论更昔洛韦治疗CMV肝炎疗效好,仅少数病例出现白细胞、血小板降低,无其他毒副作用。     

Cytomegalovirus retinitis associated with acquired immunodeficiency syndrome

Background  Cytomegalovirus (CMV) retinitis is the most severe intraocular complication that results in total retinal destruction and loss of visual acuity in patients with acquired immunodeficiency syndrome (AIDS). This study aimed to investigate the fundus characteristics, systemic manifestations and therapeutic outcomes of CMV retinitis associated with AIDS.

Methods  It was a retrospective case series. CMV retinitis was present in 39 eyes (25 patients). Best corrected visual acuities, anterior segment, fundus features, fundus fluorescence angiography (FFA) and CD4⁺ T-lymphocyte counts of the patients with CMV retinitis associated with AIDS were analyzed. Intravitreal injections of ganciclovir (400 µg) were performed in 4 eyes (2 patients).

Results  Retinal vasculitis, dense, full-thickness, yellow-white lesions along vascular distribution with irregular granules at the border, and hemorrhage on the retinal surface were present in 28 eyes. The vitreous was clear or mildly opaque. Late stage of the retinopathy was demonstrated in 8 eyes characterized as atrophic retina, sclerotic and attenuated vessels, retinal pigment epithelium (RPE) atrophy, and optic nerve atrophy. Retinal detachment was found in 3 eyes. The average CD4⁺ T-lymphocyte count in peripheral blood of the patients with CMV retinitis was (30.6±25.3) ×10⁶/L (range, (0–85) ×10⁶/L). After intravitreal injections of ganciclovir, visual acuity was improved and fundus lesions regressed.

Conclusions  CMV retinitis is the most severe and the most common intraocular complication in patients with AIDS. For the patients with yellow-white retinal lesions, hemorrhage and retinal vasculitis without clear cause, human immunodeficiency virus (HIV) serology should be performed. Routine eye examination is also indicated in HIV positive patients.

     

更昔洛韦与阿昔洛韦治疗水痘临床疗效的对比研究

目的对比分析更昔洛韦与阿昔洛韦治疗水痘的临床疗效与安全性。方法选取2017年6月—2018年6月我院收治的110例水痘患者作为研究对象,按照随机数字表法分为阿昔洛韦组(阿昔组)与更昔洛韦组(更昔组),各55例。对比分析2组患者临床疗效,临床症状改善时间,不良反应发生情况及用药安全性等。结果治疗7d后,更昔组总有效率为96.36%,明显高于阿昔组的78.18%,差异有统计学意义(P<0.05);更昔组水痘-带状疱疹病毒转阴时间为(1.58±1.01)d,短于阿昔组的(2.92±1.06)d。此外,更昔组水疱结痂时间、退热时间、疼痛与瘙痒缓解时间也均短于阿昔组,差异均有统计学意义(P均<0.05);更昔组不良反应发生率为3.64%,低于阿昔组14.55%的不良反应发生率,差异有统计学意义(P<0.05)。结论在临床基础资料均衡的情况下,与阿昔洛韦相比,更昔洛韦治疗水痘临床总有效率更高,患者水疱结痂时间及临床症状改善时间均更短且治疗安全性更高,不良反应发生率低,具有临床推广价值。