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Journal of Clinical Virology : the... Jul 2019The natural history of cytomegalovirus (CMV) infection in transplant patients has been well established. This virus may originate from the recipient, the donor or both.... (Review)
Review
The natural history of cytomegalovirus (CMV) infection in transplant patients has been well established. This virus may originate from the recipient, the donor or both. When pre-transplant IgG antibodies in the recipient are taken into account, three types of infection are possible: primary, reactivation or reinfection. The risks of high viral load and end-organ disease are highest after primary infection and lowest after reactivation. Serial monitoring of patients by quantitative polymerase chain reaction for CMV DNA allows antiviral drugs to be deployed for pre-emptive therapy or an antiviral drug may be given prophylactically. Both of these strategies are effective, but pre-emptive therapy has the advantage that randomised allocation of a new drug or placebo given prophylactically may show a reduced need for pre-emptive valganciclovir. In this review, I will consider what has been learned from use of ganciclovir and valganciclovir and apply this information to clinical trials that have evaluated maribavir, brincidofovir and letermovir. In addition, pre-emptive therapy has the advantage of facilitating the discovery of vaccines against CMV using a pharmacodynamic approach. Briefly, patients awaiting transplantation are given vaccine or placebo pre-transplant. When they proceed to transplantation, various parameters of viral load can be compared to determine if the vaccine has an effect against CMV when compared to patients randomised to receive placebo. If there is evidence of control of CMV, this can be related to immune responses induced by the vaccine to define a correlate of protection. This review will summarise the published evidence available.
Topics: Antiviral Agents; Clinical Trials as Topic; Combined Modality Therapy; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Humans; Transplantation; Viral Load
PubMed: 31132546
DOI: 10.1016/j.jcv.2019.04.007 -
The National Medical Journal of India 2016
Topics: AIDS-Related Opportunistic Infections; Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Cytomegalovirus Retinitis; Ganciclovir; Humans; Male; Valganciclovir
PubMed: 27492038
DOI: 10.4103/0970-258x.186919 -
Expert Opinion on Drug Metabolism &... Feb 2015Among infants and immunocompromised children cytomegalovirus (CMV) is associated with significant morbidity and mortality. (Review)
Review
INTRODUCTION
Among infants and immunocompromised children cytomegalovirus (CMV) is associated with significant morbidity and mortality.
AREAS COVERED
This review describes the clinical pharmacokinetics and pharmacodynamics of ganciclovir and valganciclovir for the treatment and prevention of CMV infection in children.
EXPERT OPINION
A 24-h ganciclovir area under the concentration versus time curve (AUC₀₋₂₄) of 40 - 60 μg h/ml decreased the risk of CMV infection for adults undergoing CMV prophylaxis. For adults undergoing treatment for active CMV disease, a target AUC₀₋₁₂ of 40 - 60 μg h/ml has been suggested. The applicability of these targets to children remains uncertain; however, with the most sophisticated dosing regimens developed to date only 21% of patients are predicted to reach these targets. Moving forward, identification of optimal pediatric ganciclovir and valganciclovir dosing regimens may involve the use of an externally validated pediatric population pharmacokinetic model for empirical dosing, an optimal sampling strategy for collecting a minimal number of blood samples for each patient and Bayesian updating of the dosing regimen based on an individual patient's pharmacokinetic profile.
Topics: Adult; Animals; Antiviral Agents; Area Under Curve; Bayes Theorem; Child; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Ganciclovir; Humans; Immunocompromised Host; Infant; Valganciclovir
PubMed: 25428442
DOI: 10.1517/17425255.2015.988139 -
The Medical Journal of Australia Nov 2014Cytomegalovirus (CMV) is a highly prevalent and globally distributed virus. CMV infection in healthy adults is usually asymptomatic or causes a mild mononucleosis-like... (Review)
Review
Cytomegalovirus (CMV) is a highly prevalent and globally distributed virus. CMV infection in healthy adults is usually asymptomatic or causes a mild mononucleosis-like syndrome. CMV disease causes significant morbidity and mortality in neonates and severely immunocompromised adults. CMV disease can present with a wide range of manifestations, with colitis being the most common. The incidence of severe CMV disease in immunocompetent adults appears to be greater than previously thought, which may be partly due to immune dysfunction related to comorbidities such as kidney disease or diabetes mellitus. CMV disease can mimic an array of alternative diagnoses and pose a significant diagnostic challenge, especially in immunocompetent adults, leading to delayed diagnosis, adverse health outcomes and unnecessary financial expense. Non-invasive testing for CMV is widely available and can facilitate early diagnosis if used appropriately. Although limited, current evidence suggests that targeted antiviral therapy with ganciclovir or valganciclovir is appropriate for severe CMV disease in immunocompetent adults.
Topics: Adult; Antiviral Agents; Comorbidity; Cytomegalovirus Infections; Delayed Diagnosis; Ganciclovir; Humans; Immunocompetence; Valganciclovir
PubMed: 25390262
DOI: 10.5694/mja14.00183 -
Blood Advances Oct 2023Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a...
Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.
Topics: Humans; Adolescent; Adult; Valganciclovir; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Histone Deacetylase Inhibitors; Neoplasm Recurrence, Local; Lymphoma, Non-Hodgkin; Lymphoma; Thrombocytopenia; Lymphoma, T-Cell
PubMed: 37530631
DOI: 10.1182/bloodadvances.2023010330 -
Current Opinion in Pediatrics Feb 2016Cytomegalovirus (CMV) is the most common cause of congenital infection in the world. Symptomatic infants are at increased risk of developing permanent sequelae,... (Review)
Review
PURPOSE OF REVIEW
Cytomegalovirus (CMV) is the most common cause of congenital infection in the world. Symptomatic infants are at increased risk of developing permanent sequelae, including sensorineural hearing loss and neurodevelopmental delay. Advances in the treatment and prevention of congenital CMV infection are a high priority nationally and globally.
RECENT FINDINGS
In symptomatic infants, antiviral therapy with 6 months of oral valganciclovir improves hearing and neurodevelopmental outcomes. Strategies to prevent congenital or maternal CMV infections, including the use of CMV hyperimmune globulin and development of a maternal vaccine, have yet to yield positive results.
SUMMARY
The clinical significance of congenital CMV infection, developments in antiviral therapy, and efforts to prevent congenital disease are herein reviewed.
Topics: Antiviral Agents; Cytomegalovirus Infections; Female; Ganciclovir; Hearing Loss, Sensorineural; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Valganciclovir
PubMed: 26709686
DOI: 10.1097/MOP.0000000000000305 -
Clinics in Perinatology Mar 2015Neonatal fungal and viral infections are associated with mortality and neurologic impairment among survivors. Advances in pharmacokinetics (PK) and pharmacodynamics (PD)... (Review)
Review
Neonatal fungal and viral infections are associated with mortality and neurologic impairment among survivors. Advances in pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial medications have led to improved dosing guidance for neonates. This article discusses the basic PK/PD properties and dosing of the most common antifungal and antiviral medications used in neonates.
Topics: Acyclovir; Amphotericin B; Antifungal Agents; Antiviral Agents; Candidiasis, Invasive; Cytomegalovirus Infections; Deoxycholic Acid; Drug Combinations; Fluconazole; Ganciclovir; Herpes Simplex; Humans; Infant; Infant, Newborn; Mycoses; Practice Guidelines as Topic; Pregnancy Complications, Infectious; Valganciclovir; Virus Diseases
PubMed: 25678004
DOI: 10.1016/j.clp.2014.10.010 -
Journal of Korean Medical Science Aug 2023The aim of this study was to capture multifaceted clinical characteristics of congenital cytomegalovirus (CMV) infection from diagnosis to treatment using a...
BACKGROUND
The aim of this study was to capture multifaceted clinical characteristics of congenital cytomegalovirus (CMV) infection from diagnosis to treatment using a multidisciplinary approach including obstetrics, pediatrics, pathology, and otorhinolaryngology-head and neck surgery.
METHODS
This is a retrospective study including 30 consecutive cases of congenital CMV infection that were diagnosed at a single tertiary hospital located in Seoul, Korea from January 2009 to December 2020. Congenital CMV infection was defined as a positive result by polymerase chain reaction from urine, saliva or cerebrospinal fluid or positive CMV IgM from neonatal blood sampled within 3 weeks after birth. All cases were analyzed with respect to whole clinical characteristics from diagnosis to treatment of congenital CMV by a multidisciplinary approach including prenatal sonographic findings, maternal immune status regarding CMV infection, detailed placental pathology, neonatal clinical manifestation, auditory brainstem response test, and antiviral treatment (ganciclovir or valganciclovir). Long-term outcomes including developmental delay and hearing loss were also investigated.
RESULTS
The total number of births during the study period in our institution was 19,385, with the prevalence of congenital infection estimated to be 0.15%. Among 30 cases of congenital CMV, the median gestational age at delivery was 32.2 weeks [range, 22.6-40.0] and 66.7% of these infants were delivered preterm at less than 37 weeks. Suspected fetal growth restriction was the most common prenatal ultrasound finding (50%) followed by ventriculomegaly (17.9%) and abnormal placenta (17.9%), defined as thick placenta with calcification. No abnormal findings on ultrasound examination were observed in one-third of births. Maternal CMV serology tests were conducted in only 8 cases, and one case each of positive and equivocal IgM were found. The most common placental pathologic findings were chronic villitis (66.7%) and calcification (63.0%), whereas viral inclusions were identified in only 22.2%. The most common neonatal manifestations were jaundice (58.6%) followed by elevation of aspartate aminotransferase (55.2%) and thrombocytopenia (51.7%). After excluding cases for which long-term outcomes were unavailable due to death (n = 4) or subsequent follow up loss (n = 3), developmental delay was confirmed in 43.5% of infants (10/23), and hearing loss was confirmed in 42.9% (9/21) during the follow-up period. In our cohort, 56.7% (17/30) of neonates were treated for congenital CMV with ganciclovir or valganciclovir.
CONCLUSION
Our data show that prenatal findings including maternal serologic tests and ultrasound have limited ability to detect congenital CMV in Korea. Given that CMV is associated with high rates of developmental delay and hearing loss in infants, there is an urgent need to develop specific strategies for the definite diagnosis of congenital CMV infection during the perinatal period by a multidisciplinary approach to decrease the risks of neurologic impairment and hearing loss through early antiviral treatment.
Topics: Infant; Infant, Newborn; Pregnancy; Female; Humans; Child; Valganciclovir; Retrospective Studies; Placenta; Cytomegalovirus Infections; Ganciclovir; Antiviral Agents; Hearing Loss; Fetal Growth Retardation; Parturition; Immunoglobulin M
PubMed: 37582499
DOI: 10.3346/jkms.2023.38.e249 -
Expert Opinion on Pharmacotherapy Aug 2019: Human cytomegalovirus (HCMV) or human herpesvirus 5 (HHV-5) is a β-herpesvirus that causes widespread infection in nearly all members of the human population... (Review)
Review
: Human cytomegalovirus (HCMV) or human herpesvirus 5 (HHV-5) is a β-herpesvirus that causes widespread infection in nearly all members of the human population worldwide. Its persistence in humans after primary infection in a latent phase as well as a partial non-protective immune response is the basis for repeated re-activation/re-infection episodes occurring both in immunocompetent and immunocompromised subjects. In the latter patient populations, which include hematopoietic stem cell transplant (HSCT) recipients, HCMV reactivation episodes may be particularly severe, leading to both systemic and end-organ diseases. Since the 90s, at least four antiviral drugs targeting the DNA polymerase complex have been developed for the prevention and treatment of HCMV infections in transplant recipients, used as first-line (ganciclovir and valganciclovir) and second-line therapy (foscarnet and cidofovir). However, due to their toxicity and drug-resistance induction, new drugs with different targets were needed. : In 2017, a new drug named letermovir (LTV), which targets the HCMV DNA terminase complex, was licensed for prophylaxis of HCMV infections in HSCT recipients. This is the focus of this review. : LTV safety and efficacy are promising. However, long-term adverse events and the emergence of drug-resistant HCMV strains must be investigated in extended clinical trials prior to drawing final conclusions.
Topics: Acetates; Antiviral Agents; Chemoprevention; Cidofovir; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Humans; Immunocompromised Host; Quinazolines; Transplant Recipients; Transplantation Conditioning; Valganciclovir
PubMed: 31282759
DOI: 10.1080/14656566.2019.1637418 -
Hematology/oncology Clinics of North... Feb 2018Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a rare, polyclonal lymphoproliferative disorder characterized by flares of... (Review)
Review
Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a rare, polyclonal lymphoproliferative disorder characterized by flares of inflammatory symptoms, edema, cytopenias, lymphadenopathy, and splenomegaly. Diagnosis requires a lymph node biopsy. Pathogenesis is related to dysregulated inflammatory cytokines, including human and viral interleukin-6. Rituximab alone or in combination with chemotherapy, such as liposomal doxorubicin, has led to an overall survival of over 90% at 5 years. Experimental approaches to treatment include virus activated cytotoxic therapy with high-dose zidovudine and valganciclovir and targeting human interleukin-6 activity. Despite successful treatment of KSHV-MCD, patients remain at high risk for developing non-Hodgkin lymphomas.
Topics: Biopsy; Castleman Disease; Doxorubicin; Ganciclovir; Herpesvirus 8, Human; Humans; Interleukin-6; Lymph Nodes; Rituximab; Valganciclovir; Zidovudine
PubMed: 29157621
DOI: 10.1016/j.hoc.2017.09.007