-
Clinical Infectious Diseases : An... Sep 2023Encephalitis is a devastating neurologic disease often complicated by prolonged neurologic deficits. Best practices for the management of adult patients include...
Encephalitis is a devastating neurologic disease often complicated by prolonged neurologic deficits. Best practices for the management of adult patients include universal testing for a core group of etiologies, including herpes simplex virus (HSV)-1, varicella zoster virus (VZV), enteroviruses, West Nile virus, and anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody encephalitis. Empiric acyclovir therapy should be started at presentation and in selected cases continued until a second HSV-1 polymerase chain reaction test is negative. Acyclovir dose can be increased for VZV encephalitis. Supportive care is necessary for other viral etiologies. Patients in whom no cause for encephalitis is identified represent a particular challenge. Management includes repeat brain magnetic resonance imaging, imaging for occult malignancy, and empiric immunomodulatory treatment for autoimmune conditions. Next-generation sequencing (NGS) or brain biopsy should be considered. The rapid pace of discovery regarding autoimmune encephalitis and the development of advanced molecular tests such as NGS have improved diagnosis and outcomes. Research priorities include development of novel therapeutics.
Topics: Adult; Humans; Acyclovir; Herpesvirus 3, Human; Encephalitis; Brain; Nervous System Diseases; Herpesvirus 1, Human; Encephalitis, Herpes Simplex
PubMed: 37485952
DOI: 10.1093/cid/ciad306 -
JAMA Jul 2023Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a...
IMPORTANCE
Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression.
OBJECTIVE
To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022).
INTERVENTIONS
Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos.
MAIN OUTCOMES AND MEASURES
The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.
RESULTS
Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%).
CONCLUSION AND RELEVANCE
Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.
Topics: Adult; Male; Humans; Middle Aged; Female; Antiviral Agents; Valganciclovir; Cytomegalovirus; Kidney Transplantation; Cytomegalovirus Infections; Neutropenia
PubMed: 37279999
DOI: 10.1001/jama.2023.9106 -
Archives of Disease in Childhood Aug 2023Congenital human cytomegalovirus (CMV) infection is the most common congenital infection, affecting around 1 in 200 infants in high-income settings. It can have... (Review)
Review
Congenital human cytomegalovirus (CMV) infection is the most common congenital infection, affecting around 1 in 200 infants in high-income settings. It can have life-long consequences for up to one in four children, including sensorineural hearing loss and neurodisability. Despite the frequency of congenital CMV and the severity for some children, it is a little-known condition by pregnant women, families and healthcare providers. Timely diagnosis of CMV infection in pregnancy is important to facilitate consideration of treatment with valaciclovir, which may reduce the risk of transmission to the fetus or reduce the severity of the outcomes for infected infants. Recognition of features of congenital CMV is important for neonatologists, paediatricians and audiologists to prompt testing for congenital CMV within the first 21 days of life. Early diagnosis gives the opportunity for valganciclovir treatment, where appropriate, to improve outcomes for affected infants. Further research is urgently needed to inform decisions about antenatal and neonatal screening, long-term outcomes for asymptomatic and symptomatic infants, predictors of these outcomes and optimal treatment for women and infants.
Topics: Infant; Infant, Newborn; Child; Female; Pregnancy; Humans; Cytomegalovirus Infections; Valganciclovir; Pregnancy Complications, Infectious; Valacyclovir; Fetal Diseases; Hearing Loss, Sensorineural
PubMed: 36442957
DOI: 10.1136/archdischild-2022-323809 -
Transplant International : Official... 2023Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV... (Review)
Review
Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV infection may fail to respond to standard first- and second-line antiviral therapies with or without the presence of antiviral resistance to these therapies. This failure to respond after 14 days of appropriate treatment is referred to as "resistant/refractory CMV." Limited data on refractory CMV without antiviral resistance are available. Reported rates of resistant CMV are up to 18% in SOT recipients treated for CMV. Therapeutic options for treating these infections are limited due to the toxicity of the agent used or transplant-related complications. This is often the challenge with conventional agents such as ganciclovir, foscarnet and cidofovir. Recent introduction of new CMV agents including maribavir and letermovir as well as the use of adoptive T cell therapy may improve the outcome of these difficult-to-treat infections in SOT recipients. In this expert review, we focus on new treatment options for resistant/refractory CMV infection and disease in SOT recipients, with an emphasis on maribavir, letermovir, and adoptive T cell therapy.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Acetates; Ganciclovir
PubMed: 37901297
DOI: 10.3389/ti.2023.11785 -
Clinical Microbiology and Infection :... Sep 2023Cytomegalovirus (CMV) is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and haematopoietic stem cell transplantation.... (Review)
Review
BACKGROUND
Cytomegalovirus (CMV) is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and haematopoietic stem cell transplantation. Treatment of CMV disease involves a two-pronged approach with antiviral drug treatment coupled with strategies to minimize the intensity of immune suppression.
OBJECTIVES
This narrative review examines the evidence for the current treatment of CMV disease in transplant recipients, including the use of oral antiviral drugs.
SOURCES
Literature search was performed on PubMed with keywords cytomegalovirus, transplantation, ganciclovir, valganciclovir, maribavir, letermovir, cidofovir, and foscarnet.
CONTENT
Intravenous and oral valganciclovir are the standard first-line treatment of cytomegalovirus disease after transplantation. Oral maribavir has demonstrated superior efficacy and safety over CMV DNA polymerase inhibitors for the treatment of refractory or resistant CMV infection. Transplant patients with severe and life-threatening CMV disease, those with very high viral load, and patients with impaired gastrointestinal absorption should still be treated initially with intravenous antiviral drugs, including ganciclovir and foscarnet. Criteria for the safe transition from intravenous therapies to oral antiviral drugs include achieving clinical improvement and satisfactory decline in viral load. Recurrence of CMV viremia and disease is common, particularly among transplant patients who are lymphopenic and have impaired CMV-specific immunity.
IMPLICATIONS
Oral antiviral drugs for the treatment of CMV infection and disease in transplant recipients have improved the CMV landscape, because they reduce the cost and mitigate the inconvenience and risks related to prolonged hospitalization and the need for long-term intravascular access. However, their antiviral efficacy should be complemented by an intentional strategy of reducing the degree of immune suppression to allow for immunologic recovery that ensures durable control of CMV infection.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Valganciclovir; Foscarnet; Transplant Recipients; Ganciclovir; Cytomegalovirus Infections
PubMed: 36963566
DOI: 10.1016/j.cmi.2023.03.020 -
Nature Microbiology Jul 2023Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with...
Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with antiviral acyclovir treatment, most patients still experience various neurological sequelae. Here we characterize HSV-1 infection of human brain organoids by combining single-cell RNA sequencing, electrophysiology and immunostaining. We observed strong perturbations of tissue integrity, neuronal function and cellular transcriptomes. Under acyclovir treatment viral replication was stopped, but did not prevent HSV-1-driven defects such as damage of neuronal processes and neuroepithelium. Unbiased analysis of pathways deregulated upon infection revealed tumour necrosis factor activation as a potential causal factor. Combination of anti-inflammatory drugs such as necrostatin-1 or bardoxolone methyl with antiviral treatment prevented the damages caused by infection, indicating that tuning the inflammatory response in acute infection may improve current therapeutic strategies.
Topics: Humans; Herpesvirus 1, Human; Herpes Simplex; Acyclovir; Antiviral Agents; Encephalitis, Viral; Organoids
PubMed: 37349587
DOI: 10.1038/s41564-023-01405-y -
American Journal of Obstetrics and... Feb 2024Recent studies have shown that a dosage of 8 g/d of oral valacyclovir reduces substantially the vertical transmission rate of cytomegalovirus in women with primary... (Meta-Analysis)
Meta-Analysis
The effect of valacyclovir on secondary prevention of congenital cytomegalovirus infection, following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy. An individual patient data meta-analysis.
OBJECTIVE
Recent studies have shown that a dosage of 8 g/d of oral valacyclovir reduces substantially the vertical transmission rate of cytomegalovirus in women with primary cytomegalovirus infection acquired periconceptionally or during the first trimester of pregnancy. This individual patient data meta-analysis aimed to assess the effectiveness and safety of valacyclovir treatment in the secondary prevention of congenital cytomegalovirus infection.
DATA SOURCES
MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, the US registry of clinical trials (www.
CLINICALTRIALS
gov), and gray literature sources were searched from inception to March 2023.
STUDY ELIGIBILITY CRITERIA
Randomized controlled trials and quasi-randomized studies administering 8 g/d of oral valacyclovir in pregnant women with primary cytomegalovirus infection acquired periconceptionally or during the first trimester of pregnancy were included.
METHODS
All corresponding authors of the eligible studies were contacted. Cochrane's Risk of Bias 2 and Risk Of Bias In Non-randomised Studies - of Interventions tools were used for the risk of bias assessment. The result of amniocentesis was the primary outcome of interest. A 1-stage individual patient data meta-analysis was performed, using a generalized linear mixed model, clustered by the different trials. A subgroup analysis was performed, assessing separately the effect of valacyclovir in the periconceptional period and first trimester of pregnancy.
RESULTS
Overall, 3 studies were included in the analysis (n=527 women). Valacyclovir reduced the vertical transmission rate of cytomegalovirus (adjusted odds ratio, 0.34; 95% confidence interval, 0.18-0.61). This reduction was apparent for both periconceptional period (adjusted odds ratio, 0.34; 95% confidence interval, 0.12-0.96) and first-trimester (adjusted odds ratio, 0.35; 95% confidence interval, 0.16-0.76) infections. Moreover, valacyclovir reduced the rate of neonatal infection (adjusted odds ratio, 0.30; 95% confidence interval, 0.19-0.47), in both periconceptional period (adjusted odds ratio, 0.30; 95% confidence interval, 0.14-0.61) and first-trimester (adjusted odds ratio, 0.30; 95% confidence interval, 0.17-0.54) infections. Furthermore, valacyclovir reduced the rate of termination of pregnancy because of cytomegalovirus-associated severe fetal findings (adjusted odds ratio, 0.23; 95% confidence interval, 0.22-0.24). The gestational age at the initiation of treatment has a positive correlation with all outcomes. The overall prevalence of severe side effects was 2.1%.
CONCLUSION
A dosage of 8 g/d of oral valacyclovir reduced the vertical transmission rates of cytomegalovirus following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy, with a low incidence of side effects.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Cytomegalovirus Infections; Pregnancy Complications, Infectious; Pregnancy Trimester, First; Secondary Prevention; Valacyclovir
PubMed: 37473793
DOI: 10.1016/j.ajog.2023.07.022 -
Cell Stem Cell Feb 2024The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their...
The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their apical surface. Here, we describe long-term expanding organoids and air-liquid interface representing mouse and human conjunctiva. A single-cell RNA expression atlas of primary and cultured human conjunctiva reveals that keratinocytes express multiple antimicrobial peptides and identifies conjunctival tuft cells. IL-4/-13 exposure increases goblet and tuft cell differentiation and drastically modifies the conjunctiva secretome. Human NGFR+ basal cells are identified as bipotent conjunctiva stem cells. Conjunctival cultures can be infected by herpes simplex virus 1 (HSV1), human adenovirus 8 (hAdV8), and SARS-CoV-2. HSV1 infection was reversed by acyclovir addition, whereas hAdV8 infection, which lacks an approved drug therapy, was inhibited by cidofovir. We document transcriptional programs induced by HSV1 and hAdV8. Finally, conjunctival organoids can be transplanted. Together, human conjunctiva organoid cultures enable the study of conjunctival (patho)-physiology.
Topics: Humans; Mice; Animals; Conjunctiva; Goblet Cells; Epithelium; Interleukin-13; Homeostasis; Organoids
PubMed: 38215738
DOI: 10.1016/j.stem.2023.12.008 -
Archives of Disease in Childhood Oct 2023Primary infection with varicella zoster virus (VZV) in the final 3 weeks of pregnancy may cause transplacental infection and neonatal varicella. Infants are most at risk... (Review)
Review
Primary infection with varicella zoster virus (VZV) in the final 3 weeks of pregnancy may cause transplacental infection and neonatal varicella. Infants are most at risk of severe disease if born from 5 days before to 2 days after onset of the maternal varicella rash. Administration of post-exposure prophylaxis with varicella zoster immunoglobulin and treatment of varicella with aciclovir for those at highest risk of progression to severe disease is advised. Universal vaccination against VZV significantly reduces the incidence of neonatal varicella.
PubMed: 37907245
DOI: 10.1136/archdischild-2022-324820