Valganciclovir e ganciclovir para profilaxia e tratamento de infecções pelo citomegalovírus (CMV) em pacientes imunossuprimidos pelo HIV / Valganciclovir and ganciclovir for prophylaxis and treatment of cytomegalovirus (CMV) infections in HIV-immunosuppressed patients

INTRODUÇÃO: O HIV é o agente causador da Síndrome da Imunodeficiência Adquirida (Aids), uma doença sexualmente transmissível, que compromete o sistema imunológico dos pacientes. Estima-se haver mais de um milhão de pessoas vivendo com HIV/Aids (PVHA) no Brasil. Entre as possíveis comorbidades associada à Aids estão as infecções oportunistas e, dentre elas, as infecções causadas pelo CMV. Infecções por CMV em pacientes imunocompetentes normalmente são brandas e não demandam tratamento medicamentoso. Entretanto, em pacientes imunocomprometidos, a infecção pode ser grave, acometendo a retina (retinopatia) e o trato gastrointestinal. O ganciclovir intravenoso (IV) ou o valganciclovir para tratamento de CMV em PVHA podem ser utilizados, mas nenhuma dessas tecnologias foi avaliada pela Conitec para esta indicação. PERGUNTA: Valganciclovir e ganciclovir são eficazes, efetivos, seguros e custo-efetivos para o tratamento e profilaxia de infecções por CMV em pacientes adultos e crianças imunossuprimidos pelo HIV? EVIDÊNCIAS CLÍNICAS: A análise das evidências disponíveis na literatura permitiu constatar a eficá

Cytokine Dynamics and Herpesvirus Interactions in Pediatric Liver and Kidney Transplant Recipients: The Distinct Behavior of HCMV, HHV6, HHV7 and EBV.

Pediatric solid organ transplant (SOT) recipients face a challenging balance between immunosuppression and graft rejection. While Epstein-Barr Virus (EBV) and cytomegalovirus (HCMV) are known contributors to post-transplant lymphoproliferative disease and graft rejection, respectively, the roles of herpesvirus 6 and 7 (HHV6 and HHV7) and the impact of these herpesviruses on cytokine levels remain unclear, leading to gaps in clinical practice. In this associative study, we measured 17 cytokines using a Bio-Plex assay in a meticulously curated plasma sample pool (N = 158) from pediatric kidney and liver transplant recipients over a one-year follow-up period. The samples included virus-negative and virus-positive cases, either individually or in combination, along with episodes of graft rejection. We observed that the elevation of IL-4, IL-8, and IL-10 correlated with graft rejection. These cytokines were elevated in samples where HCMV or HHV6 were detected alone or where EBV and HHV7 were co-detected. Interestingly, latent EBV, when detected independently, exhibited an immunomodulatory effect by downregulating cytokine levels. However, in co-detection scenarios with ß-herpesviruses, EBV transitioned to a lytic state, also associating with heightened cytokinemia and graft rejection. These findings highlight the complex interactions between the immune response and herpesviruses in transplant recipients. The study advocates for enhanced monitoring of not only EBV and HCMV but also HHV6 and HHV7, providing valuable insights for improved risk assessment and targeted interventions in pediatric SOT recipients.

Guillain-Barré Syndrome and Encephalitis Following a Cytomegalovirus Infection in an Immunocompetent Adult: A Case Report.

BACKGROUND Cytomegalovirus (CMV) is a common herpesvirus that often causes asymptomatic or mild infections. In immunocompromised patients, CMV can lead to severe complications, including Guillain-Barre syndrome (GBS) and encephalitis. While these conditions have been described in the immunocompetent population, simultaneous presentation of CMV-associated GBS and encephalitis in such individuals has not been previously reported. CASE REPORT We present a case of a 58-year-old woman with poorly controlled diabetes who developed concurrent GBS and encephalitis following a CMV infection. The patient experienced bilateral ascending paraparesis 1 week after self-limited gastrointestinal symptoms. Despite initial treatment with plasma exchange therapy, her condition deteriorated with altered mental status and generalized tonic-clonic seizures, necessitating orotracheal intubation. Laboratory analysis revealed the presence of CMV in her cerebrospinal fluid. After treatment with further sessions of plasma exchange therapy and ganciclovir, her muscular strength in the extremities improved. However, she developed acute lung edema and failed extubation, leading to cardiorespiratory arrest with neurological sequelae. Palliative care was institutionalized, and she died 2 weeks later due to pneumonia. CONCLUSIONS This case highlights an unusual clinical presentation of overlapping CMV-associated GBS and encephalitis in an immunocompetent individual, with diabetes as the only identified risk factor. It underscores the importance of considering CMV as a potential etiological factor in such complex cases and the need for prompt diagnosis to improve patient outcomes. Further research is warranted to explore the underlying mechanisms and implications of this rare overlapping neurological manifestation.

Cytomegalovirus in Adenoma and Carcinoma Lesions: Detecting Mono-Infection and Co-Infection in Salivary Glands.

Salivary glands' neoplasms are hard to diagnose and present a complex etiology. However, several viruses have been detected in these neoplasms, such as HCMV, which can play a role in certain cancers through oncomodulation. The co-infections between HCMV with betaherpesviruses (HHV-6 and HHV-7) and polyomaviruses (JCV and BKV) has been investigated. The aim of the current study is to describe the frequency of HCMV and co-infections in patients presenting neoplastic and non-neoplastic lesions, including in the salivary gland. Multiplex quantitative polymerase chain reaction was used for betaherpesvirus and polyomavirus quantification purposes after DNA extraction. In total, 50.7% of the 67 analyzed samples were mucocele, 40.3% were adenoma pleomorphic, and 8.9% were mucoepidermoid carcinoma. Overall, 20.9% of samples presented triple-infections with HCMV/HHV-6/HHV-7, whereas 9.0% were co-infections with HCMV/HHV-6 and HCMV/HHV-7. The largest number of co-infections was detected in pleomorphic adenoma cases. All samples tested negative for polyomaviruses, such as BKV and JCV. It was possible to conclude that HCMV can be abundant in salivary gland lesions. A high viral load can be useful to help better understand the etiological role played by viruses in these lesions. A lack of JCV and BKV in the samples analyzed herein does not rule out the involvement of these viruses in one or more salivary gland lesion subtypes.

Universal and Expanded Screening Strategy for Congenital Cytomegalovirus Infection: Is Pool Testing by a Rapid Molecular Test in Saliva a New Choice in Developing Countries?

BACKGROUND: Several screening strategies for identifying congenital CMV (cCMV) have been proposed; however, the optimal solution has yet to be determined. We aimed to determine the prevalence of cCMV by universal screening with saliva pool testing and to identify the clinical variables associated with a higher risk of cCMV to optimize an expanded screening strategy. METHODS: We carried out a prospective universal cCMV screening (September/2022 to August/2023) of 2186 newborns, analyzing saliva samples in pools of five (Alethia-LAMP-CMV®) and then performed confirmatory urine CMV RT-PCR. Infants with risk factors (small for gestational age, failed hearing screening, HIV-exposed, born to immunosuppressed mothers, or <1000 g birth weight) underwent expanded screening. Multivariate analyses were used to assess the association with maternal/neonatal variables. RESULTS: We identified 10 infants with cCMV (prevalence: 0.46%, 95% CI 0.22-0.84), with significantly higher rates (2.1%, 95% CI 0.58-5.3) in the high-risk group (p = 0.04). False positives occurred in 0.09% of cases. No significant differences in maternal/neonatal characteristics were observed, except for a higher prevalence among infants born to non-Chilean mothers (p = 0.034), notably those born to Haitian mothers (1.5%, 95% CI 0.31-4.34), who had higher odds of cCMV (OR 6.82, 95% CI 1.23-37.9, p = 0.04). Incorporating maternal nationality improved predictive accuracy (AUC: 0.65 to 0.83). CONCLUSIONS: For low-prevalence diseases such as cCMV, universal screening with pool testing in saliva represents an optimal and cost-effective approach to enhance diagnosis in asymptomatic patients. An expanded screening strategy considering maternal nationality could be beneficial in resource-limited settings.

Cytomegalovirus infection and disease in systemic lupus erythematosus patients at a high-complexity hospital in southwestern Colombia.

Cytomegalovirus (CMV) infection and disease is a condition usually described in immunocompromised patients, but among them, those with connective tissue diseases are poorly represented. Here we present the clinical, laboratory characteristics, management and outcomes of systemic lupus erythematosus (SLE) patients who presented with a CMV infection/disease to a high complexity hospital in southwestern Colombia between 2011 and 2020. 16 SLE patients were found to have a CMV infection. SLE was predominantly characterized by renal involvement (10 patients; 62.50%), and 14 patients (87.5%) were receiving steroids previous to the CMV infection. The entire sample required hospital admission, mainly related to acute kidney injury, and nine patients were admitted to the intensive care unit (ICU). Gastrointestinal organ damage was the most common CMV disease manifestation. All patients received ganciclovir, five of them (31.25%) suffered from septic shock, and seven (43.75%) died. Age ≥38 years and the presence of septic shock at admission were correlated to the mortality outcome. To our knowledge, this is the first publication evaluating SLE patients with CMV infection/disease in a Colombian population.

T-Cell Immune Responses in Newborns and Long-Term Sequelae in Congenital Cytomegalovirus Infection (CYTRIC Study).

OBJECTIVE: The objective of this study was to assess the role of T-lymphocyte immune responses in newborns with congenital cytomegalovirus (CMV) infection (cCMV) and their potential association with the development of long-term sequelae. STUDY DESIGN: A multicenter, prospective study from 2017 to 2022 was conducted across 8 hospitals in Spain. Blood samples were collected within the first month of life from neonates diagnosed with cCMV. Intracellular cytokine staining was employed to evaluate the presence of CMV-specific interferon-gamma (IFN-γ)-producing CD8+ and CD4+ T lymphocytes (CMV-IFN-γ-CD8+/CD4+) using flow cytometry. The development of sequelae, including hearing loss and neurologic impairment, was assessed during follow-up. RESULTS: In total, 64 newborns were included; 42 infants (65.6%) had symptomatic cCMV. The median age at the last follow-up visit was 25.3 months (IQR 20.1-34.4). Eighteen infants had long-term sequelae (28.1%), predominantly hearing loss (20.3%) and neurologic disorders (15.6%). No relationship was observed between total count or percentage of CMV-specific IFN-γ-CD8+ or CD4+ lymphocytes and long-term sequelae. Multivariable analysis demonstrated an association between lower total lymphocyte count and long-term sequelae (aOR 0.549, 95% CI: 0.323-0.833), which requires further study. CONCLUSIONS: CMV-specific IFN-γ-CD4+ and CD8+ T-lymphocyte responses in neonates with cCMV were not predictive of long-term sequelae.

Molecular Detection and Genetic Diversity of Cytomegaloviruses and Lymphocryptoviruses in Free-Roaming and Captive African Green Monkeys (Chlorocebus sabaeus).

To date, limited information is available on cytomegalovirus (CMV) and lymphocryptovirus (LCV) from Chlorocebus monkeys. We report here high detection rates of herpesviruses in free-roaming African green monkeys (AGMs, Chlorocebus sabaeus) (26.4%, 23/87) and in captive AGMs (75%, 3/4) with respiratory disease on the Caribbean Island of St. Kitts. LCV (81.25%) was more prevalent than CMV (18.75%) in the AGMs. Applying a bigenic PCR approach (targeting DNA polymerase (DPOL) and glycoprotein B (gB) genes), long sequences were obtained from representative AGM CMV (KNA-SD6) and LCV (KNA-E4, -N6 and -R15) samples, and mixed LCV infections were identified in KNA-N6 and -R15. The nucleotide (nt) sequence (partial DPOL-intergenic region-partial gB) and partial DPOL- and gB-amino acid (aa) sequences of AGM CMV KNA-SD6 were closely related to Cytomegalovirus cercopithecinebeta5 isolates from grivet monkeys, whilst those of AGM LCV KNA-E4 and -N6 (and E4-like gB of KNA-R15) were more closely related to cognate sequences of erythrocebus patas LCV1 from patas monkey than other LCVs, corroborating the concept of cospeciation in the evolution of CMV/LCV. On the other hand, the partial DPOL aa sequence of KNA-R15, and additional gB sequences (N6-gB-2 and R15-gB-2) from samples KNA-N6 and -R15 (respectively) appeared to be distinct from those of Old World monkey LCVs, indicating LCV evolutionary patterns that were not synchronous with those of host species. The present study is the first to report the molecular prevalence and genetic diversity of CMV/LCV from free-roaming/wild and captive AGMs, and is the first report on analysis of CMV nt/deduced aa sequences from AGMs and LCV gB sequences from Chlorocebus monkeys.

Congenital CMV infection in a Brazilian neonatal intensive care unit: high prevalence among twin newborns.

BACKGROUND: Cytomegalovirus (CMV) is one of the most important pathogens associated with congenital infection worldwide. Most congenital CMV-infected infants are asymptomatic at birth; however, some can develop delayed sequelae, especially hearing loss. METHODS: This study aimed to investigate the prevalence of congenital CMV infection in a neonatal intensive care unit in a low-income region of Brazil. The objectives extended to identifying associated factors, assessing the clinical status of infected newborns, and undertaking a two-year follow-up to discern potential long-term consequences in the affected infants. This cross-sectional prospective study enrolled newborns up to three weeks of life requiring intensive medical care. We employed a convenience sampling method to include 498 newborns and 477 mothers in the study. Categorical variables underwent analysis employing Fisher's exact test, whereas the examination of continuous variables involved the Mann‒Whitney test. RESULTS: CMV DNA was detected in saliva/urine samples from 6 newborns (1.21%), confirming congenital infection. We noted a significantly greater incidence (OR: 11.48; 95% CI: 2.519-52.33; p = 0.0094) of congenital infection among twins (7.14%) than among nontwins (0.66%). The twin patients exhibited discordant infection statuses, suggesting that only one of the babies tested positive for CMV. Most of the infected children were born to mothers who initiated sexual activity at a younger age (p = 0.0269). Only three out of the six newborns diagnosed with CMV infection underwent comprehensive clinical assessments and received continuous follow-up until they reached two years of age. Only one of the children had weight and height measurements below the norm for their age, coupled with developmental delays. CONCLUSIONS: The prevalence of congenital CMV infection among newborns admitted to the NICU was low and similar to that in the general population. However, we found a significantly greater incidence of congenital CMV infection in twins than in singletons. Interestingly, the twin-infected patients exhibited discordant infection statuses, suggesting that CMV was present in only one of the babies. We also found that most of the infected children were born to mothers who initiated sexual activity at a younger age. Diagnostic accessibility and comprehensive surveillance programs are imperative for effectively managing and preventing congenital CMV infections.

Infección congénita por citomegalovirus, hipoacusia y tamizaje neonatal. Una actualización / Congenital cytomegalovirus infection, hearing loss and newborn screening. An update

El citomegalovirus congénito (CMVc) es la infección congénita más común y la principal causa no genética de hipoacusia congénita. Gran parte de los recién nacidos (RN) con CMVc sintomático desarrolla secuelas graves permanentes, donde la hipoacusia es la más frecuente. Sin embargo, el 90% de los casos se presenta en forma asintomática, pudiendo desarrollar secuelas auditivas tardías. El diagnóstico precoz de CMVc requiere un alto índice de sospecha. Actualmente, técnicas eficientes para su detección están disponibles, lo que facilita el diagnóstico en las primeras 3 semanas de vida. La terapia antiviral es la primera línea de tratamiento para el CMVc sintomático, logrando buenos resultados auditivos. A pesar de los avances en los métodos de detección y beneficios del tratamiento, los RN no son tamizados para CMVc. El tamizaje selectivo de CMVc en pacientes que no pasan el screening auditivo facilita la intervención precoz en los casos identificados, pero no permite detectar el número significativo de niños que presenta hipoacusia de aparición tardía. El tamizaje universal permite hacer seguimiento auditivo a los pacientes en riesgo de desarrollar hipoacusia sensorioneural (HSN) por CMVc, identificando así los casos de hipoacusia de aparición tardía, pero la costo-efectividad es aún controversial. Es necesario avanzar en una estrategia local para el tamizaje de CMVc, buscando reducir su impacto a nivel nacional.

Congenital cytomegalovirus (cCMV) is the most common congenital infection and the main non-genetic cause of congenital hearing loss. A significant number of newborns (NB) with symptomatic cCMV will develop permanent serious sequelae, being hearing loss the most frequent. However, 90% of the cases are asymptomatic and may develop late auditory sequelae. Early diagnosis of cCMV requires a high index of suspicion. Currently, efficient detection techniques for its detection are available, which facilitates diagnosis within the first 3 weeks of life. Antiviral therapy is the first line of treatment for symptomatic cCMV, achieving good hearing results. Despite advances in detection methods and the benefits of antiviral therapy, NB are not routinely screened for cCMV. Selective screening for cCMV in patients who fail newborn hearing screening facilitates early intervention in identified cases but fails to detect a significant number of children with late onset hearing loss. Universal screening allows hearing follow up in patients at risk of developing sensorineural hearing loss (SNHL) due to cCMV, thus identifying late-onset hearing loss cases, but cost-effectiveness is still controversial. It is necessary to advance in a local strategy for cCMV screening, aiming to reduce its national impact.

Aetiological molecular identification of sexually transmitted infections that cause urethral discharge syndrome and genital ulcer disease in Brazilian men: a nationwide study.

BACKGROUND: Little is known about the aetiology of urethral discharge syndrome (UDS) and genital ulcer disease (GUD) in Brazil due to limited access to laboratory tests and treatment based mainly on the syndromic approach. OBJECTIVES: To update Brazilian treatment guidelines according to the current scenario, the first nationwide aetiological study for UDS and GUD was performed. METHODS: Male participants with urethral discharge (UD) and/or genital ulcer (GU) reports were enrolled. Sample collection was performed by 12 sentinel sites located in the five Brazilian regions. Between 2018 and 2020, 1141 UD and 208 GU samples were collected in a Universal Transport Medium-RT (Copan). A multiplex quantitative PCR kit (Seegene) was used to detect UD: Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), M. hominis (MH), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV), Ureaplasma parvum (UP), U. urealyticum (UU) and another kit to detect GU: cytomegalovirus (CMV), Haemophilus ducreyi (HD), herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), lymphogranuloma venereum (LGV), Treponema pallidum (TP) and varicella-zoster virus (VZV). RESULTS: In UD samples, the frequency of pathogen detection was NG: 78.38%, CT: 25.6%, MG: 8.3%, UU: 10.4%, UP: 3.5%, MH: 3.5% and TV: 0.9%. Coinfection was assessed in 30.9% of samples, with 14.3% of NG/CT coinfection. The most frequent pathogen identified in GU was HSV2, present in 40.8% of the samples, followed by TP at 24.8%, LGV and CMV at 1%, and HSV1 at 0.4%. Coinfection of TP/HSV2 was detected in 4.4% of samples. VZV and HD were not detected. In 27.7% of the GU samples, no pathogen was detected. CONCLUSION: This study provided the acquisition of unprecedented data on the aetiology of UDS and GUD in Brazil, demonstrated the presence of a variety of pathogens in both sample types and reaffirmed the aetiologies known to be most prevalent globally.

Guías Latinoamericanas de Infecciones Congénitas y Perinatales de la Sociedad Latinoamericana de Infectología Pediátrica (SLIPE). Parte II / Latin American Guidelines on Congenital and Perinatal Infections from the Latin-American Society of Pediatric Infectious Diseases (SLIPE). Part II

Las infecciones perinatales son una causa de morbilidad, tanto fetal como neonatal, y que compromete la salud de la mujer embarazada, por lo que su diagnóstico, tratamiento, e intento de eliminación son una prioridad en América Latina y el Caribe. Este documento representa la segunda entrega realizada por expertos en la región dentro de la Sociedad Latinoamericana de Infectología Pediátrica (SLIPE), brindando una mirada actualizada en el manejo de las infecciones congénitas y entrega herramientas para detectar posibles momentos estratégicos de intervención y cambio en el manejo de las infecciones congénitas.

Perinatal infections are a major cause of morbidity and mortality in the fetus, neonate, and the health of the pregnant woman. Diagnosis, treatment, and the search for elimination of these diseases are a priority in Latin America and the Caribbean. This document represents the second delivery by a group of experts in the region inside the Latin-American Society of Pediatric Infectious Diseases (SLIPE), presenting a up-to-date look into the management of congenital infectious diseases and give a tool to detect possible strategic sceneries and a change in the management of congenital infections in our region.

Valganciclovir in Infants with Hearing Loss and Clinically Inapparent Congenital Cytomegalovirus Infection: A Nonrandomized Controlled Trial.

OBJECTIVE: To assess the efficacy of valganciclovir in infants with hearing loss and clinically inapparent congenital cytomegalovirus infection (cCMV), as there is no consensus on treatment of this group. STUDY DESIGN: A nationwide, nonrandomized controlled trial, comparing 6 weeks of oral valganciclovir to no treatment in infants with cCMV, recruited after newborn hearing screening resulted in referral to an audiologist. The choice whether to treat was left to parents of subjects. Eligible subjects were full term infants aged <13 weeks with sensorineural hearing loss and diagnosed with cCMV through dried blood spot testing. The primary outcome, measured by linear and ordinal logistic regression, was change in best-ear hearing from baseline to follow-up at 18-22 months of age. RESULTS: Thirty-seven participants were included in the final analysis, of whom 25 were in the treatment group and 12 in the control group. The majority of subjects in both groups had neuroimaging abnormalities, which were mostly mild. Hearing deterioration was more likely in the control group compared with the treatment group (common OR 0.10, 95% CI 0.02-0.45, P = .003). Mean best-ear hearing deteriorated by 13.7 dB in the control group, compared with improvement of 3.3 dB in the treatment group (difference 17 dB, 95% CI 2.6 - 31.4, P = .02). CONCLUSIONS: We investigated treatment in children with hearing loss and clinically inapparent cCMV. Although our study was nonrandomized, it is the first prospective and controlled trial in this population. Valganciclovir-treated children with hearing loss and inapparent cCMV had less hearing deterioration at 18 through 22 months of age than control subjects. EUDRACT REGISTRY NUMBER: 2013-003068-30.

Oral Valganciclovir Initiated Beyond 1 Month of Age as Treatment of Sensorineural Hearing Loss Caused by Congenital Cytomegalovirus Infection: A Randomized Clinical Trial.

OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.

Guillain-Barré syndrome following primary cytomegalovirus infection in a patient with liver transplantation.

We present the case of a man in his 60s with a 5-month medical history of deceased donor liver transplantation, who developed Guillain-Barré syndrome (GBS) secondary to a primary cytomegalovirus (CMV) infection. This was confirmed by molecular tests and serology antibodies that ruled out other frequent aetiologies. Therapy with intravenous immunoglobulin and valganciclovir was started and the patient gradually improved over the weeks. GBS is the most common aetiology of paralysis worldwide, and it is an autoimmune-mediated neuropathy that is frequently caused by a preceding infection. Few cases of GBS have been reported in the context of liver transplant recipients, and those related to CMV infection are extremely rare. This case highlights the importance of considering GBS as a possible differential diagnosis in patients with solid organ transplantation, and it contributes to the knowledge of other infrequent aetiologies of this condition.

A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial.

BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor. METHODS: This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease. RESULTS: There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054). CONCLUSIONS: De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.

QuantiFERON-CMV as a Predictor of CMV Events During Preemptive Therapy in CMV-seropositive Kidney Transplant Recipients.

BACKGROUND: Prevention of cytomegalovirus (CMV) infection after kidney transplantation is costly and burdensome. METHODS: Given its promising utility in risk stratification, we evaluated the use of QuantiFERON-CMV (QFCMV) and additional clinical variables in this prospective cohort study to predict the first clinically significant CMV infection (CS-CMV, ranging from asymptomatic viremia requiring treatment to CMV disease) in the first posttransplant year. A cost-effectiveness analysis for guided prevention was done. RESULTS: One hundred adult kidney transplant recipients, CMV IgG + , were given basiliximab induction and maintained on steroid/mycophenolate/tacrolimus with weekly CMV monitoring. Thirty-nine patients developed CS-CMV infection (viral syndrome, n = 1; end-organ disease, n = 9; and asymptomatic viremia, n = 29). A nonreactive or indeterminate QFCMV result using the standard threshold around day 30 (but not before transplant) was associated with CS-CMV rates of 50% and 75%, respectively. A higher QFCMV threshold for reactivity (>1.0 IU interferon-γ/mL) outperformed the manufacturer's standard (>0.2 IU interferon-γ/mL) in predicting protection but still allowed a 16% incidence of CS-CMV. The combination of recipient age and type of donor, along with posttransplant QFCMV resulted in a prediction model that increased the negative predictive value from 84% (QFCMV alone) to 93%. QFCMV-guided preemptive therapy was of lower cost than preemptive therapy alone ( P < 0.001, probabilistic sensitivity analysis) and was cost-effective (incremental net monetary benefit of 210 USD) assuming willingness-to-pay of 2000 USD to avoid 1 CMV disease. CONCLUSIONS: Guided CMV prevention by the prediction model with QFCMV is cost-effective and would spare from CMV surveillance in 42% of patients with low risk for CS-CMV.