Epidemiology and Outcome of Ganciclovir-Resistant Cytomegalovirus Infection After Solid Organ Transplantation: A Single Transplant Center Experience in Thailand.

BACKGROUND: Data on drug-resistant cytomegalovirus (CMV) infection in solid organ transplantation (SOT) are not often reported from resource-limited settings. We aimed to investigate the epidemiology and outcomes of this infection in SOT recipients at our institution. METHODS: This was a retrospective study conducted from January 2012 to May 2015. We included all SOT recipients who were suspected for drug-resistant CMV infection. Genotypic assay for UL97 gene mutation was analyzed by real-time polymerase chain reaction. Patients were reviewed for demographic data, clinical presentation, virologic data, treatment, and outcomes. RESULTS: The population consisted of 18 (12 kidney, 6 liver) SOT recipients with a median age of 20 years (interquartile range [IQR], 1-49); 44% were male. Anti-CMV resistance testing was analyzed at a median time of 23 days (IQR, 14-33) after initiation of anti-CMV therapy with a median CMV load of log 3.79 copies/mL (IQR, 3.37-4.58). During a median period of 2 years (IQR, 1-3), 6 SOT recipients were identified with UL97 gene mutation in codon 460, conferring ganciclovir (GCV) resistance. Patients with UL97 gene mutation had a longer mean duration of CMV DNAemia compared with those without mutation (263 vs 107 days; P = .04). All patients received high-dose GCV. Two patients received foscarnet and cidofovir. Two patients died (non-CMV-related), and 4 patients developed opportunistic infections other than CMV. CONCLUSIONS: GCV-resistant CMV infection in SOT recipients is an emerging clinical problem in resource-limited country. Those with UL97 mutation CMV infection have prolonged duration of CMV DNAemia. Clinicians should be aware of this condition when caring for SOT recipients.

Recurrent Herpes Labialis in Adults: New Tricks for an Old Dog.

Herpes labialis remains a common worldwide affliction. Recent advances in understanding the basic pathogenesis have led to new therapeutic intervention, both on-label and off-label. Aside from reducing the duration and symptomatology of acute outbreaks, another goal of treatment is to decrease the frequency of future episodes. Oral and topical acyclovir and its analogues are the mainstay of both chronic suppressive and episodic therapy. A new muco-adhesive formulation of acyclovir provides a decrease in outbreaks, probably due to a diminution of herpesvirus load in all reservoir sites. Acyclovir-resistant strains are rare in immunocompetent hosts; parenteral foscarnet and cidofovir are administered in this situation. Parenteral acyclovir is the drug of choice for eczema herpeticum, which may begin as herpes labialis in an atopic dermatitis patient. Thermotherapy may be beneficial, and a certified device to deliver heat is available outside the United States.

J Drugs Dermatol. 2017;16(3 Suppl):s49-53.

The alpha-herpesviridae in dermatology : Varicella zoster virus.

The second part of this publication deals with varicella zoster virus (VZV) and presents an overview of new, rare, and atypical clinical manifestations, including photolocalized varicella, hemorrhagic bullae during varicella, the implication of VZV in immunoglobulin A vasculitis, VZV-related alopecia, ulcerative varicella skin lesions, childhood herpes zoster (HZ), prolonged prodromal pains, recurrent HZ, VZV implication in burning mouth syndrome, verruciform VZV lesions, the significance of satellite lesions during HZ, and late HZ complications, either neurological or internal. Furthermore, certain associations between the occurrence of HZ and subsequent internal pathologies, as well as risk factors for HZ and new developments in vaccination against HZ will be addressed.

Cidofovir / Cidofovir

INTRODUCCIÓN: La cistitis hemorrágica (HC) es una complicación grave del trasplante de células madre hematopoyéticas (HSCT) y presenta una incidencia variable del 7 al 70%(1). Generalmente, la HC es una complicación dolorosa que prolonga la internación, aumenta el requerimiento de transfusiones de sangre y en sus formas severas puede causar obstrucción del tracto urinario. La ocurrencia de HC ha sido asociada con mayor mortalidad. Los factores predisponentes, incluyen: HSCT alogénico, edad avanzada en el trasplante, enfermedad de injerto contra huésped (GVHD), trombocitopenia, coagulopatía e infección viral. Las HC se clasifican en dos tipos: (1) inicio temprano, que ocurre dentro de las primeras 48 a 72 horas después de HSCT y generalmente debido a los efectos tóxicos de la quimioterapia; (2) inicio tardío, ocurre luego de 72 horas, usualmente de causa infecciosa, particularmente el virus BK (BKV)(2). La HC asociada al virus BK (BKV-HC) es una complicación frecuente luego de un trasplante alogénico de células hematopoyéticas. De acuerdo a su presentación clínica, se clasifica en diferentes grados de severidad: Grado I: Hematuria microscópica; Grado II: Hematuria macroscópica; Grado III: Hematuria macroscópica con presencia de coágulos en orina; Grado IV: Hematuria macroscópica con presencia de coágulos en orina y alteración de la función renal secundaria a obstrucción de las vías urinarias. TECNOLOGÍA: El cidofovir es un nucleósido análogo de citosina activo contra varios virus ADN. Ejerce una inhibición selectiva en la síntesis de ADN, suprimiendo la replicación viral. La EMA (European Medicines Agency) y la FDA (Food and Drug Administration) lo aprobaron para el tratamiento de la retinitis por citomegalovirus en adultos con síndrome de inmunodeficiencia adquirida y sin alteración de la función renal. El cidofovir causa nefrotoxicidad con daño a células tubulares proximales y aumento de la creatinina sérica. La nefrotoxicidad es muy frecuente y es dosis dependiente. La mayoría de las veces se recomienda la asociación con Probenecid vía oral para mantener una concentración plasmática útil de cidofovir que permita su administración semanal, disminuyendo la penetración y acumulación del cidofovir en las células renales y así atenuar su nefrotoxicidad. La modalidad de tratamiento varía en dosis y vías de administración. La vía intravesical se usa en casos de viruria con baja viremia y daño renal previo, aunque su efectividad es cuestionada. Por vía endovenosa, se usa en una dosis variable de 0,5 a 5 mg/kg, una o dos veces por semana. La elección de dosis y frecuencia depende de la severidad del cuadro y fundamentalmente, de la nefrotoxicidad. OBJETIVO: Evaluar la eficacia y seguridad de cidofovir en la HC por BK virus post HSCT. DISCUSIÓN: El cidofovir constituye una tecnología sanitaria experimental para el tratamiento de la HC-BKV. Se han utilizado diferentes dosis y vías de administración. La evidencia disponible sugiere que su eficacia para el tratamiento oscila entre el 60 y 100%. En el diseño de los estudios se constata que sólo en uno fue comparado vs tratamiento convencional pero fue un estudio descriptivo de dos grupos independientes. En este estudio, el cidofovir no fue superior en respuesta clínica ni en duración de la HC. La respuesta clínica de la HC en cuanto a disminución de hematuria, eliminación de coágulos y disuria, no siempre correlaciona con una significativa disminución de la carga viral en sangre o en orina. La mitad de los pacientes pos-trasplante presenta viruria y no desarrollan HC. Este aspecto no permite definir con absoluta certeza el grado de responsabilidad del virus ni del cidofovir en el desarrollo de la HC y su tratamiento. Se describen varios eventos adversos pero el más importante y serio, es la nefrotoxicidad que se relaciona con las dosis utilizadas y la duración del tratamiento. La función renal basal y la viruria/viremia deben ser tenidas en cuenta en la prescripción y vía de administración del cidofovir. Los criterios de elección de la ruta de administración local o sistémica no fueron expresamente definidos pero se relacionan con la ubicación del virus, la nefrotoxicidad y la función renal previa. El contexto peri-trasplante agrega varios tratamientos potencialmente nefrotóxicos que se suman al cidofovir y a la nefropatía derivada de la obstrucción urinaria por HC, lo que impone la necesidad de un extremo cuidado para la función renal. RECOMENDACIONES: El cidofovir es una opción terapéutica en el tratamiento de la HC-BKV y requiere control estricto de la función renal dado el alto riesgo de nefrotoxicidad. Es por ahora un tratamiento experimental. Su uso adecuado y en ámbito adecuado, es de estricta responsabilidad del médico tratante.

Herpes simplex virus and varicella zoster virus: recent advances in therapy.

PURPOSE OF REVIEW: The mainstay of antiviral therapy for the alpha-herpesviruses [herpes simplex virus (HSV)-1, HSV-2, and varicella zoster virus (VZV)] over the past 40 years has been the nucleoside analogues such as aciclovir. Although conventional antiviral therapy has reduced mortality in severe disease, novel agents are needed to address the emergence of resistance and toxicity associated with current second-line therapy. Treatment and prophylaxis of VZV and HSV reactivations remains a challenge. RECENT FINDINGS: A number of compounds have recently been evaluated in human clinical trials, amongst them brincidofovir, an intracellularly acting derivative of cidofovir currently undergoing phase III trials. The helicase-primase inhibitors are a new class of antiviral agent and may circumvent resistance to existing agents. Amenamevir and pritelivir are two examples of these agents that have been evaluated clinically along with novel nucleoside analogues such as valomaciclovir and FV-100. Tenofovir, an agent used in HIV and hepatitis B therapy, may also have a role in the prevention of HSV-2 acquisition and reduce viral shedding. SUMMARY: Although several novel antiviral agents have undergone clinical trials in recent years, all are yet to gain licensure. Brincidofovir appears to be the candidate with most promise for adoption into routine practice in the near future.

Disseminated adenovirus disease in heart transplant recipient presenting with conjunctivitis.

We report a 65-year-old heart transplant recipient who presented with conjunctivitis, likely acquired from a family member who worked at a daycare center during an outbreak of conjunctivitis. He developed a severe adenoviral pneumonitis, which was successfully treated with intravenous cidofovir combined with a reduction of immunosuppression.

Trends in the management of recurrent respiratory papillomatosis in Japan.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) has historically been and still continues to be a difficult disease to treat. The present study aimed to characterize current practices in the treatment of RRP in Japan. METHODS: A questionnaire was posted to the Department of Otolaryngology of all 80 central university hospitals in Japan. RESULTS: A total of 56 universities responded to the survey. Regarding the use of surgical instruments, a trend toward a preference for lasers (50 hospitals) rather than a microdebrider (16 hospitals) or cold instruments (20 hospitals) was observed. Among the 50 hospitals frequently performing laser surgery, a carbon dioxide (CO2) laser was most commonly used, followed by a potassium-titanyl-phosphate (KTP) laser. The most favored adjuvant therapy was traditional Chinese medicine. Eight of the 56 university hospitals had an experience of using cidofovir, involving a total of 28 patients. CONCLUSION: The present study demonstrated the current trends in the management of RRP based on a questionnaire survey in a geographical area other than the US and UK for the first time. Treatment trends were generally similar in all three areas except for the least popular use of cidofovir in Japan.

Treatment of BK virus-associated nephropathy with CMX001 after kidney transplantation in a young child.

NC, with renal failure secondary to bilateral dysplastic kidneys, received an LRD renal transplant (tx) at 17 months of age. Her early post-tx course was complicated by persistently elevated blood polyoma BK virus DNA loads. A protocol biopsy at six months post-transplant revealed BKVAN. Blood viral loads did not respond to decreased immunosuppression or treatment with ciprofloxacin and leflunomide. Six months post-tx, her serum creatinine began to rise and we sought experimental therapy to prevent the loss of her graft. At seven months post-tx, with FDA approval under an eIND, the patient was started on a 36-wk course of treatment with the investigational drug. The patient is now more than 24 months after stopping treatment with CMX. BKV viral DNA loads remain at low, but still detectable levels. Urine viral loads have declined, but remain elevated. EBV DNA loads become undetectable. The patient's serum creatinine has declined back to a baseline of 0.5-0.7 mg/dL and has been stable for two yr. Renal function was preserved in association with the use of CMX001 to treat BKV nephropathy in a young pediatric kidney transplant recipient. There were no serious adverse events associated with the use of CMX001. This novel medication may be of value in the treatment of BKVAN in pediatric renal transplant recipients.

Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses.

CMX001 (hexadecyloxypropyl-cidofovir, Brincidofovir) is a broad spectrum, lipid conjugate of cidofovir that is converted intracellularly into the active antiviral, cidofovir diphosphate. The lipid conjugation results in oral bioavailability, higher intracellular concentrations of active drug, lower plasma concentrations of cidofovir and increased antiviral potency against dsDNA viruses.

In vitro characterization of a nineteenth-century therapy for smallpox.

In the nineteenth century, smallpox ravaged through the United States and Canada. At this time, a botanical preparation, derived from the carnivorous plant Sarracenia purpurea, was proclaimed as being a successful therapy for smallpox infections. The work described characterizes the antipoxvirus activity associated with this botanical extract against vaccinia virus, monkeypox virus and variola virus, the causative agent of smallpox. Our work demonstrates the in vitro characterization of Sarracenia purpurea as the first effective inhibitor of poxvirus replication at the level of early viral transcription. With the renewed threat of poxvirus-related infections, our results indicate Sarracenia purpurea may act as another defensive measure against Orthopoxvirus infections.

Sapacitabine for cancer.

INTRODUCTION: Sapacitabine is an orally bioavailable nucleoside analog prodrug that is in clinical trials for hematologic malignancies and solid tumors. The active metabolite of sapacitabine, CNDAC (2'-C-cyano-2'-deoxy-1-ß-D-arabino-pentofuranosylcytosine), exhibits the unique mechanism of action of causing single-strand breaks (SSBs) after incorporation into DNA, which are converted into double-strand breaks (DSBs) when cells enter a second S-phase. CNDAC-induced DSBs are predominantly repaired through homologous recombination (HR). Cells deficient in HR components are greatly sensitized to CNDAC. Therefore, sapacitabine could be specifically effective against tumors that are deficient in this repair pathway. AREAS COVERED: This review summarizes results from supporting evidence for the mechanisms of action of sapacitabine, its preclinical activities and the current results of clinical trials in a variety of cancers. The novel action mechanism of sapacitabine is discussed, with a view to validate it as a chemotherapeutic drug targeting malignancies with defects in HR. EXPERT OPINION: Knowledge of CNDAC mechanism identifies tumors that may be sensitized to sapacitabine, thus enabling a personalized treatment strategy. It also creates the opportunity to overcome resistance to current front-line therapies and identify synergistic interactions with known anticancer drugs. The results of such investigations may provide rationales for the design of sapacitabine-based clinical trials.

Medical and surgical approaches to vulvar intraepithelial neoplasia.

Vulvar intraepithelial neoplasia (VIN) is a precursor to invasive vulvar carcinoma. The two major types of VIN, usual and differentiated, differ in epidemiology, pathogenesis, clinical manifestations, pathology, and malignant potential. Usual VIN commonly occurs in younger women. It is associated with human papillomavirus and tends to have multifocal and multicentric involvement. Differentiated VIN is frequently associated with benign vulvar dermatoses such as lichen sclerosus and lichen simplex chronicus. It occurs in older women and typically is unifocal and unicentric. Clinicians must have a high suspicion for VIN, which is diagnosed by biopsy. Surgical excision has been the standard treatment in order to prevent progression to invasive disease. The objectives of treatment have expanded to include preservation of normal vulvar function and anatomy. Therefore, management options are being investigated, including topical therapy, laser excision and vaporization, and photodynamic therapy. All can be effective in both eliminating disease and maintaining relatively normal-appearing and functioning anatomy.

Can zinc be an adjuvant therapy for juvenile onset recurrent respiratory papillomatosis?

OBJECTIVES: To report a severe case of juvenile onset recurrent respiratory papillomatosis (JORRP) controlled by zinc replacement therapy. To review the contemporary adjuvant therapies used in JORRP. METHODS: The trial of zinc was described in terms of its effect on the inter-surgical interval, site score and clinical symptoms. Long-term follow-up with dose adjustment was detailed. Articles reporting trials of adjuvant therapies over the past 20 years were reviewed in terms of regimen used, mode of assessment, side effects and final outcome. RESULTS: Zinc was effective in decreasing the severity of the disease, the rate of relapse and the need for surgery. There was an obvious relation between the dose used and the degree of improvement. Prolonged treatment seems to be needed to sustain the positive effect. No side effects were noticed over a 45-month follow-up period. The literature does support the role of zinc in modulating the immune system. Eight adjuvant therapies were reviewed as published in 40 reports. Interferon was the most used substance. It is definitely effective but often associated with relapse upon discontinuation. The effect of cidofovir was favorable yet not dramatic as initially expected. Other less commonly used therapies showed humble effects. The HspE7 vaccine seems to be promising awaiting further trials. CONCLUSIONS: Zinc replacement therapy may benefit JORRP patients with zinc deficiency and should be investigated in more cases. Several adjuvant therapies are available for use in JORRP. They are generally beneficial though mostly not curative.

In vivo imaging of cidofovir treatment of cowpox virus infection.

Variola virus and other members of the genus Orthopoxviruses constitute a prominent bioterrorism and public health threat. Treatment with the anti-viral drug cidofovir inhibits replication of orthopoxviruses in vitro and in vivo. In this study, we visualized the effect of cidofovir on viral kinetics in orthopoxvirus infected mice by using whole-body fluorescence imaging (FI). We engineered a cowpox virus (CPV) expressing the enhanced green fluorescent protein (GFP). Single-step growth curves and calculated 50% lethal doses (LD(50)) of wild-type CPX (Wt-CPV) and GFP-expressing CPX (GFP-CPV) were comparable. Whole-body FI first detected GFP fluorescence in the mesenteric tissue of untreated animals on post-infection day (PID) 1. On PID 3 GFP signal was detected throughout the mesentery, in all abdominal organs by PID 5 and in most major organs, except for the heart and brain by PID 6. Infected animals treated with 25mg/kg of cidofovir also began showing signs of viral replication on PID 1, however, the fluorescent signal was limited only to discrete foci throughout the course of the infection. This work describes the first use of an established Orthopox model of infection to evaluate drug efficacy and track virus progression on a macroscopic level.

Evaluation of the L-stereoisomeric nucleoside analog troxacitabine for the treatment of acute myeloid leukemia.

Troxacitabine (BCH-4556; [-]-2'-deoxy-3'-oxacytidine) is a synthetic dioxolane that represents the first nucleoside analog with an L-isomer configuration to have shown important cytotoxic activity. Troxacitabine was obtained by exchanging the sulfur endocyclic atom with oxygen in the structure of lamivudine (3TC). Its unnatural stereochemistry renders it insensitive to some mechanisms of resistance of tumor cells to D-nucleosides, such as deamination by deoxycytidine deaminase and decreased active uptake by nucleoside transporters. These characteristics make troxacitabine a suitable alternative for patients with acute myelogenous leukemia as a potential way for overcoming resistance to ara-C therapy, which is the mainstay of acute myelogenous leukemia therapy at present. Clinically significant activity has been reported in Phase I studies in patients with advanced hematologic malignancies and has prompted troxacitabine to enter a series of Phase II trials in patients with refractory and relapsed acute myelogenous leukemia.

Drug evaluation: sapacitabine--an orally available antimetabolite in the treatment of cancer.

Cyclacel Pharmaceuticals, under license from Sankyo Co, is developing the prodrug sapacitabine for the potential treatment of cancer. Sankyo initiated phase I trials prior to Cyclacel's acquisition, and phase Ib trials are currently in progress.

Clinical and in vitro evaluation of cidofovir for treatment of adenovirus infection in pediatric hematopoietic stem cell transplant recipients.

Post-hematopoietic stem cell transplantation (HSCT) adenovirus infections were identified in 31 of 204 consecutive pediatric HSCT patients, 18 of whom had severe manifestations of infection. Cidofovir treatment led to clinical improvement in 8 of 10 patients with severe infection and to virologic clearance in 9 patients. In vitro susceptibility to cidofovir was demonstrated in 12 clinical adenovirus isolates. Cidofovir is a promising treatment option for this population.

Current state of immunotherapy for bladder cancer.

Bacillus Calmette-Guerin (BCG) has been shown to be the most effective agent for the treatment of superficial bladder cancer since its approval by the US Food and Drug Administration for the treatment of carcinoma in situ of the bladder in 1990. Recently, augmentation of BCG immunotherapy with interferon-alpha2b and other agents is emerging as salvage therapy for those patients who fail initial treatment. This review summarizes the role of various immunotherapeutic agents in the treatment of bladder cancer, with special emphasis on the appropriate administration and schedule of BCG therapy as well as salvage with the combination of BCG with interferon-alpha2b.