Valganciclovir: oral prevention and treatment of cytomegalovirus in the immunocompromised host

Herpes virus infections, particularly those caused by cytomegalovirus (CMV), lead to significant and, sometimes severe, clinical problems for the immunocompromised host. As effective agents have become available, several treatment and prevention strategies have evolved over the past decade, first in intra-venous form and more recently, as oral preparations. Valganciclovir, the valine ester of ganciclovir, is an orally administered, potent, antiviral agent active against all herpes viruses. When taken orally, valganciclovir has much-improved bioavailability compared with oral ganciclovir and achieves ganciclovir exposures similar to intravenous ganciclovir. Clinical trials evaluating the safety and efficacy of valganciclovir for the treatment of new AIDS-associated CMV retinitis showed equivalency to intravenous ganciclovir and prevented progression of quiescent disease. In solid organ recipients, once-daily valganciclovir has been proven equivalent to oral ganciclovir for the prevention of CMV infection. The high bioavailability and convenient dosing formulation make valganciclovir an attractive option for these indications.     

Antiviral treatment of cytomegalovirus infection and resistant strains

This review discusses the management of resistant cytomegalovirus and prevention strategies for fatal therapy failures. Five drugs, ganciclovir/valganciclovir, cidofovir, foscarnet and fomivirsen, have been approved so far for the treatment of human cytomegalovirus (HCMV) diseases. Except for fomivirsen, all of the approved drugs share the same target molecule, the viral DNA polymerase. The emergence of drug-resistant HCMV has also been reported for all of them. For optimal care of patients, the clinical virologist has to provide the most meaningful assays for monitoring of therapy and early detection of emerging drug-resistant HCMV. Additionally, a quantitative drug monitoring would be helpful. New antiviral agents are urgently needed with less adverse effects, good oral bioavailability and possibly novel targets or mechanisms of action to avoid cross-resistance and to improve the ability to suppress the selection of resistant virus strains by combination therapy. Compounds like maribavir, leflunomide and artesunate, which exhibit anti-HCMV activity in vitro and in patients need to be evaluated in clinical studies. Besides these, new therapy approaches like immunotherapy or new diagnostic techniques like pyrosequencing have to be considered in the future.     

Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation

Introduction: Cytomegalovirus (CMV) is a common opportunistic infection that causes significant morbidity and preventable mortality after solid-organ and allogeneic hematopoietic stem cell transplantation.

Areas covered: Current strategies of pharmacological treatment of CMV in solid-organ and hematologic stem cell transplantation are reviewed. The role of the newly approved drug, letermovir, and other novel investigational compounds is discussed. The complementary role of viral and immunologic monitoring in guiding the optimal role of pharmacologic agents on the management of CMV after transplantation is highlighted. Advances in immunotherapeutics are highlighted.

Expert commentary: With advances in therapeutic and diagnostic modalities, the management of CMV infection and disease after transplantation continues to evolve. The authors provide a succinct yet comprehensive review of the current prevention and treatment for CMV infection and disease in transplant recipients. The role of the newly approved drug, letermovir, for CMV prevention is highlighted in the context of current prevention strategies after allogeneic hematopoietic stem cell transplantation. The emerging role of cell-mediated immunologic monitoring, which complements the established function of viral load testing, is emphasized. Finally, the integration of novel antiviral therapies, standardized molecular tests, immunologic assays, and immunotherapeutics are discussed.     

Cytomegalovirus treatment options in immunocompromised patients

Cytomegalovirus (CMV) infection was recognised in congenitally infected infants in the first half of the 20th century. Following the increased use of immunosuppressive regimens for bone marrow and solid organ transplantation, various manifestations of CMV disease were recognised. Milder symptoms included fever, anorexia and malaise but severe symptoms included pneumonitis, hepatitis, gastrointestinal ulceration, choreoretinitis and encephalopathy, all with a high morbidity or mortality. With the onset of the AIDS epidemic, manifestations of CMV became evident, predominantly retinitis. Ganciclovir used intravenously has been the principal anti-CMV agent investigated. However, ganciclovir has problems with suboptimal efficacy, toxicity, poor oral bioavailability and evolution of resistant strains. Additional studies have been performed on foscarnet and cidofovir, although the use of both have been limited by their nephrotoxicity. Combination therapy with ganciclovir and foscarnet for resistant strains has been used. There are promising newer drugs like the methylenecyclopropane nucleoside analogues and benzimidazole. The most novel compound is the antisense oligonucleotide fomivirsen that has been evaluated principally in CMV retinitis. The role of immunotherapy with either immunoglobulin prophylaxis or the novel adoptive immunotherapy needs further evaluation.     

更昔洛韦联合中药复方治疗婴儿巨细胞病毒性肝炎的疗效观察

目的:研究中药复方联合更昔洛韦治疗婴儿巨细胞病毒性肝炎的临床疗效。方法:按随机分组法将60名巨细胞病毒性肝炎患儿分为2组,对照组30例,治疗组30例。2组均使用更昔洛韦治疗。治疗组在此基础上加用中药复方治疗。4周后复查血清TBIL、ALT、AST、TBA、γ-GT,观察肝脾回缩情况,并将2组患儿住院时间进行比较。结果:治疗4周后,治疗组血清TBIL、ALT、AST、TBA明显下降,γ-GT明显升高,与对照组比较有显著差异(P<0.05或P<0.01)。治疗组肝脾回缩情况明显优于对照组。治疗组住院时间明显短于对照组。结论:更昔洛韦联合中药复方治疗婴儿巨细胞病毒性肝炎疗效好,住院时间短。     

Letermovir for the prevention of cytomegalovirus infection in adult cytomegalovirus-seropositive hematopoietic stem cell transplant recipients

ABSTRACT

Introduction: Allogeneic hematopoietic cell transplants (allo-HCT) recipients are at the high-risk of reactivation of cytomegalovirus (CMV), and reactivation is associated with significant morbidity and mortality. Although available anti-CMV therapies may be effective for the prevention of CMV, they are plagued by unacceptable toxicities that prohibit their use in the post-transplant period. Recently studied CMV-active agents, such as maribavir and brincidofovir, failed to reduce the incidence of CMV infection in HCT recipients. Letermovir represents the first agent in the non-nucleoside 3,4 dihydro-quinazoline class of CMV viral terminase complex inhibitors, with activity solely against CMV. The positive results from the recently published Phase III study of letermovir for prevention of CMV infection in CMV-seropositive allo-HCT recipients led to its approval as a prophylactic agent for CMV in multiple countries.

Areas covered: In this review, we will evaluate this novel agent with a focus on letermovir mechanism of action, pharmacokinetics and metabolism, clinical efficacy, and safety and toxicities.

Expert commentary: With the introduction of letermovir, prevention of CMV infection in allo-HCT recipients may shift considerably, from a predominantly preemptive strategy to one that utilizes this novel therapy for prophylaxis.     

Diagnosis and treatment of fungal infections in allogeneic stem cell and solid organ transplant recipients

Importance of the field: Invasive fungal diseases (IFD) are severe complications in patients receiving immunosuppression after solid organ or allogeneic stem cell transplantation. Extensive study has been conducted on therapeutic strategies for IFD in neutropenic patients, mostly those with hematological malignancy. There is an ongoing discussion on whether these studies may be applied to transplant patients as well.

Areas covered in this review: We have reviewed relevant literature on transplantation and clinical mycology of the last 20 years and selected articles relevant for today's treatment decisions. This article reports on the epidemiology of IFD in transplant recipients and current antifungal drugs in the context of tansplantation medicine. For invasive aspergillosis and invasive candidiasis, we give a detailed report of current clinical evidence.

What the reader will gain: This review is intended as a quick-start for clinicians and other care providers new to transplant care and as an update for experienced transplant physicians. In a field in which evidence is scarce and conflicting, we provide evidence-based strategies for diagnosing and treating the most relevant IFD in transplant recipients.

Take home message: Physicians treating transplant patients should maintain a high level of awareness towards IFD. They should know the local epidemiology of IFD to make the optimal decision between current diagnostic and therapeutic strategies. Prophylaxis or early treatment should be considered given the high mortality of IFD.     

金叶败毒颗粒防治豚鼠巨细胞病毒宫内感染

目的：利用豚鼠巨细胞病毒（guinea pig cytomegalovirus．GPCMV）宫内感染模型，探究金叶败毒颗粒防治GPCMV宫内感染的有效性和安全性。方法：①选择无感染史孕早期豚鼠．随机分为3组．感染组（30只）：腹腔接种GPCMV；治疗组（30只）：腹腔接种GPCMV＋灌胃给予中药金叶败毒颗粒；空白对照组（30只）：腹腔灌胃生理盐水。20d后处死豚鼠．采集血液及各脏器组织．检测各组豚鼠的感染情况。②随机选取受孕后昆明小鼠．分为3组．治疗组（30只）：灌胃给予金叶败毒颗粒；阳性对照组（30只）：给予致畸阳性对照药维生素A；空白对照组（30只）：给予温水。追踪母鼠一般情况及胎子生长发育状况。结果：①感染组中93．33％（28／30）出现病毒血症的征象．3．33％（1/30）死亡；治疗组和空白对照组无任何感染征象。感染组和治疗组血GPCMV DNA阳性率分别为100％（30/30）和46．67％（14／30），差异有极显著性（P〈0.01）。②昆明小鼠于器官发生期（孕1～18d）给药并不增加子代生长发育异常的风险，对孕鼠也无明显不良作用。结论：金叶败毒颗粒具有良好的抗GPCMV感染效能，对亲子代均无明显不良反应及致畸效应．因而有望成为孕期防治宫内感染的理想用药。     

Immunomodulation and pharmacological strategies in the treatment of graft-versus-host disease

Background: Allogeneic hematopoietic stem cell transplantation offers great promise for the treatment of a variety of diseases including malignancies and other diseases of hematopoietic origin. However, morbidity and mortality due to graft-versus-host disease (GVHD) remain a major barrier to its application. Objective: This review will provide an overview of the pathophysiology of GVHD and discuss the recent advances in GVHD management in both preclinical and clinical studies. Methods: An extensive literature search on PubMed from 1995 to 2008 was performed. Results/conclusion: There has been much progress in our understanding of GVHD and finding new means to control acute GVHD. While these approaches hold promise, as yet none has been able to replace the standard methods we may use routinely to decrease the incidence of the condition.     

卡泊芬净在器官移植术后侵袭性真菌感染病人中的应用

目的对卡泊芬净治疗器官移植术后侵袭性真菌感染的疗效进行评价。方法采用病例对照研究方法,选择我院器官移植术后出现侵袭性真菌感染病人100例,分为3组。卡泊芬净组36例,氟康唑组36例,两性霉素B组28例,分别予卡泊芬净、氟康唑和两性霉素B治疗,观察抗真菌治疗疗效。结果卡泊芬净组、氟康唑组和两性霉素B组抗真菌治疗的有效率分别为76%、81%和67%,3组疗效无显著差异(P>0.05)。卡泊芬净组与氟康唑组、两性霉素B组用药过程中的不良反应发生率分别为6%、6%和14%。结论卡泊芬净对于器官移植术后病人侵袭性真菌感染有明显的治疗作用,疗效与两性霉素B和氟康唑相当。     

Prevention and treatment of HIV infection in neonates: evidence base for existing WHO dosing recommendations and implementation considerations

Introduction: Antiretroviral drugs are used in neonates for prevention and treatment of HIV infection. Use of antiretrovirals to prevent perinatal HIV transmission is well established. Early identification of neonates infected with HIV and rapid initiation of combination antiretroviral treatment during the neonatal period is now recommended by WHO and DHHS. However, few antiretrovirals are available in formulations suitable for neonates and there are limited safety and pharmacokinetic data for most antiretrovirals in neonates.

Areas covered: We summarize existing neonatal antiretroviral safety and pharmacokinetic information and discuss implementation considerations for programs providing antiretrovirals to neonates and young infants.

Expert commentary: Antiretrovirals currently recommended by WHO for use in neonates are zidovudine, lamivudine, lopinavir/ritonavir, nevirapine, and raltegravir. Significant implementation challenges exist to the widespread use of these antiretrovirals in neonates. Optimal, feasible treatment of HIV-exposed and HIV-infected newborns will require development of practical neonatal dosage forms and their study in neonates for a wide range of antiretrovirals.     

Melphalan: old and new uses of a still master drug for multiple myeloma

The treatment of multiple myeloma has seen significant changes from the initial use of melphalan to the introduction of stem cell transplantation and, most recently, to the era of novel targeted agents. Melphalan still remains as a reference drug for combination regimens, including emerging newer therapeutic options, either used at a standard dose for initial or salvage treatments in patients who are not eligible for more intensive therapies, or in conjunction with new molecules within high-dose chemotherapy programs. In this review, the authors analyze old and novel regimens, including melphalan for the treatment of newly diagnosed or relapsed/resistant patients with multiple myeloma in the clinical settings of standard chemotherapy, as well as autologous or allogeneic stem cell transplantation.     

Necitumumab: a new option for first-line treatment of squamous cell lung cancer

Introduction: First-line treatment with platinum-based chemotherapy has been the standard treatment for non-small-cell lung cancer (NSCLC) during the past decades. The development of new targeted drugs based on molecular alterations (EGFR, ALK, and ROS1) has led to important outcome benefits, but not for squamous cell carcinoma (SCC). However, the aberrant function of the EGFR pathway in SCC may be important in the development of the tumor and has been explored in preclinical and clinical studies as a potential target.

Areas covered: Necitumumab is a human IgG1 anti-EGFR antibody that binds to the receptor and inhibits further pathway activation, thereby inhibiting cell differentiation, proliferation and migration. The phase III SQUIRE trial was a randomized study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone for first-line stage IV squamous NSCLC, showing a higher overall survival and better disease control with the addition of necitumumab. Despite the good results, the lack of robust predictive biomarkers makes the selection of the patients who will benefit the most complex.

Expert opinion: Necitumumab plus cisplatin-gemcitabine is a first-line treatment option in SCC that improves overall survival and preserves the patient’s quality of life with a manageable toxicity profile.     

Efficacy and safety of low-dose valganciclovir for prevention of cytomegalovirus disease in renal transplant recipients: a single-center, retrospective analysis

STUDY OBJECTIVE: To evaluate the safety and efficacy of valganciclovir 450 mg/day for 6 months for cytomegalovirus (CMV) prophylaxis in renal transplant recipients. DESIGN: Single-center, retrospective analysis. SETTING: Urban, academic medical center. PATIENTS: Fifty-eight patients who received de novo renal transplants from August 1, 2001-November 21, 2002. INTERVENTION: Valganciclovir 450 mg/day was administered to all renal transplant recipients at risk for CMV disease. Therapy was begun postoperatively and was dose adjusted to renal function. MEASUREMENTS AND MAIN RESULTS: Data collected from renal transplant recipients were demographics, immunosuppressive and antiviral drug therapy, and occurrence of CMV disease, acute rejection, allograft loss, and hematologic adverse events. Donor (D)/recipient (R) CMV serostatus was 37.9% D+/R+, 29.3% D-/R+, 17.3% D+/R-, and 15.5% D-/R-. Antithymocyte globulin (ATG) was administered to 62.1% of patients. Most of the transplant recipients received triple immunosuppression as maintenance therapy. Median follow-up was 20 months. The frequency of CMV disease was 1.7% within 6 months after transplantation and 5.2% at any point after transplantation. All patients who developed CMV disease were D+/R- and had received ATG. Leukopenia and thrombocytopenia associated with valganciclovir were seen in 28% and 24% of patients, respectively. One patient developed acute cellular rejection. No graft losses or deaths occurred. Early discontinuation of valganciclovir occurred in 20% of patients secondary to severe, persistent leukopenia, thrombocytopenia, and/or diarrhea. None of these patients developed CMV disease. CONCLUSION: A high rate of CMV disease was noted among the D+/R- population. Administration of ATG as an induction agent also increased the frequency of CMV disease. Despite the low dosage of valganciclovir, hematologic adverse events were common. However, valganciclovir, administered at 450 mg/day for 6 months, was effective and relatively safe for prophylaxis of CMV disease in renal transplant recipients.     

The cancer stem cell paradigm: a new understanding of tumor development and treatment

Importance of the field: Cancer is the second leading cause of death in the United States, and therefore remains a central focus of modern medical research. Accumulating evidence supports a ‘cancer stem cell’ (CSC) model – where cancer growth and/or recurrence is driven by a small subset of tumor cells that exhibit properties similar to stem cells. This model may provide a conceptual framework for developing more effective cancer therapies that target cells propelling cancer growth.

Areas covered in this review: We review evidence supporting the CSC model and associated implications for understanding cancer biology and developing novel therapeutic strategies. Current controversies and unanswered questions of the CSC model are also discussed.

What the reader will gain: This review aims to describe how the CSC model is key to developing novel treatments and discusses associated shortcomings and unanswered questions.

Take home message: A fresh look at cancer biology and treatment is needed for many incurable cancers to improve clinical prognosis for patients. The CSC model posits a hierarchy in cancer where only a subset of cells drive malignancy, and if features of this model are correct, has implications for development of novel and hopefully more successful approaches to cancer therapy.     

心血管疾病新药阿齐沙坦酯的药理与临床评价

阿齐沙坦酯(azilsartan medoxomil)是一种血管紧张素II受体拮抗剂,用于治疗高血压,可与其他抗高血压药物联用。本文参照美国FDA有关该药的申报资料,对其药理作用、药代动力学、临床评价、安全性评价及药物相互作用等进行综述。     

Use of HIV-1 p24 as a sensitive, precise and inexpensive marker for infection, disease progression and treatment failure

HIV RNA is an acknowledged marker of disease activity and predictive of progression, while the p24 antigen is considered unsuitable. This is at odds with the fact that viral pathogenesis is usually mediated by proteins. One might expect that p24, if analyzed properly, might even be superior to RNA. This hypothesis was investigated in clinical studies using a sensitive and precise p24 test (heat-mediated immune complex dissociation with signal amplification-boosted ELISA). This test was as sensitive and specific as the polymerase chain reaction (PCR) for viral RNA (200–400 copy detection), an overall better predictor of CD4 decline and survival, while RNA prevailed in predicting AIDS. The lower costs of p24 testing also permit a closer monitoring of patients with an earlier detection of anti-retroviral treatment failures.     

Darunavir/cobicistat for the treatment of HIV-1: a new era for compact drugs with high genetic barrier to resistance

Introduction: Cobicistat-boosted darunavir is a boosted protease inhibitor in a fixed-dose combination to be approved for the treatment of human immunodeficiency virus type1 infection. It contains darunavir, a well-known protease inhibitor with a good efficacy and safety profile, and the new pharmacokinetic enhancer cobicistat. The convenience of this combination in a single pill makes this compound easier to take, thus improving adherence.

Areas covered: PubMed and www.clinicaltrials.gov were searched with the term “darunavir/cobicistat” for all clinical trials conducted up to date, as well as for those ongoing and to be opened in the near future as well as for pharmacology data. A review of abstracts from major infectious diseases (particularly those dedicated to human immunodeficiency disease) and pharmacology conferences from 2010 to 2015 was also conducted.

Expert opinion: improving adherence, particularly by minimizing pill burden with convenient formulations (i.e., fixed-dose combination), is one of the major objectives of modern antiretroviral treatment of patients with human immunodeficiency virus disease. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels for several antiretrovirals. Darunavir co-administered with low-dose ritonavir, in combination with other antiretrovirals, is recommended in several guidelines for treatment of patients with human immunodeficiency disease. Darunavir/cobicistat fixed-dose combination allows for a once-daily treatment regimen with a reduced pill burden. This new co formulation makes this compound easier to take, thus improving adherence.     

自体造血干细胞回输治疗Ⅰ型糖尿病2例

目的观察采用自体造血干细胞回输治疗Ⅰ型糖尿病的临床疗效。方法提取自体造血干细胞后,行T淋巴系统清除,再行干细胞回输,重建T淋巴系统,以清除原免疫系统对胰岛细胞的自身免疫反应,恢复胰岛细胞功能。结果2例患儿分别于干细胞回输后第14天、第20天停用胰岛素,安全出院。随访7个月,各项检查指标均正常。结论T淋巴系统清除和自体造血干细胞重建治疗为临床治疗Ⅰ型糖尿病提供了一种新方法,近期疗效好。