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

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.

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.

Valganciclovir modulates the tumor necrosis factor axis molecules expression and CD4+ T-cell subsets in disseminated Kaposi Sarcoma patients.

Valganciclovir (VGC) was used in a randomized clinical trial in patients with disseminated Kaposi Sarcoma/human immunodeficiency virus (DKS/HIV) as add-on therapy to evaluate the proinflammatory axis tumor necrosis factor (TNF) and its receptors (TNFRs) in T cells. Two treatment schedules were used: an experimental regime (ER) and a conventional treatment (CT). Mononuclear cells from patients with DKS/HIV were obtained at baseline (W0), 4 (W4), and 12 weeks (W12). Ten DKS/HIV patients received CT (antiretroviral therapy [cART]) and 10 ER (valganciclovir [VGC] initially, plus cART at the fourth week). HIV+ without KS and HIV- patient groups were included as controls. Correlation between T-cell subsets and HHV-8 viral load (VL) and a multivariate linear regression was performed. Data showed that DKS/HIV patients have an increased frequency of CD8+ T cells, which display a high density of CD8 expression. The ER scheme increases naïve and central memory CD4+ T cells at W4 and W12 of follow-up and induces a balanced distribution of activated CD4+ T-cell subsets. Moreover, ER decreases solTNFR2 since W4 and CT decreased the transmembrane forms of TNF axis molecules. Although CT induces a positive correlation between HHV-8 VL and TNFRs, the use of ER positively correlates with TNF and TNFRs levels through follow-up and a moderate correlation with HHV-8 VL and TNF soluble levels. In conclusion, VGC, as an add-on therapy in DKS/HIV patients, gradually modulates the activation of CD4+ T-cell subsets and the TNF/TNFRs axis, suggesting a better regulation of the inflammatory status.

Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study.

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.

Impact of valganciclovir therapy on severe IRIS-Kaposi Sarcoma mortality: An open-label, parallel, randomized controlled trial.

INTRODUCTION: High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with Severe Immune Reconstitution Inflammatory Syndrome (Severe-IRIS-KS), which can occur after initiating cART, and leads to high mortality, particularly in patients with pulmonary involvement. We investigate if valganciclovir (as an anti-HHV-8 agent) initiated before cART reduces the mortality associated with Severe-IRIS-KS and the incidence of Severe-IRIS-KS. METHODS: Open-label parallel-group randomized clinical trial in AIDS cART naïve patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node, or gastrointestinal involvement, lymphedema, or ≥30 skin lesions. In the experimental group (EG), patients received valganciclovir 900 mg BID four weeks before cART and continued until week 48; in the control group (CG), cART was initiated on week 0. Non-severe-IRIS-KS was defined as: an increase in the number of lesions plus a decrease of ≥one log10 HIV-VL, or an increase of ≥50cells/mm3 or ≥2-fold in baseline CD4+cells. Severe-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia. RESULTS: 40 patients were randomized and 37 completed the study. In the ITT analysis, at 48 weeks, total mortality was the same in both groups (3/20), severe-IRIS-KS attributable mortality was 0/20 in the EG, compared with 3/20 in the CG (p = 0.09), similar to the per-protocol analysis: 0/18 in the EG, and 3/19 in the control group (p = 0.09). The crude incidence rate of severe-IRIS-KS was four patients developed a total of 12 episodes of Severe-IRIS-KS in the CG and two patients developed one episode each in the EG. Mortality in patients with pulmonary KS was nil in the EG (0/5) compared with 3/4 in the CG (P = 0.048). No difference was found between groups in the number of non-S-IRIS-KS events. Among survivors at week 48, 82% achieved >80% remission. CONCLUSIONS: Although mortality attributable to KS was lower in the EG the difference was not statistically significant.

Síndrome de Evans asociada a infección por citomegalovirus en una niña de 13 meses / Evans Syndrome Associated With Cytomegalovirus Infection In A 13-Month-Old Girl

Introducción: El síndrome de Evans es un desorden autoinmune poco frecuente, caracterizado por el descenso de al menos dos líneas celulares hemáticas. Las publicaciones del síndrome de Evans e infección por citomegalovirus resultan escasas. Objetivo: Examinar el caso de una niña con síndrome de Evans e infección activa por citomegalovirus que respondió favorablemente a la terapia antiviral. Presentación del caso: Niña de 13 meses con antecedentes de prematuridad y bajo peso al nacer, que acudió a consulta por presentar palidez y equimosis en tórax, abdomen y extremidades. En los exámenes de laboratorio se encontró trombocitopenia y anemia severa con prueba de Coombs directo positiva. Recibió pulsos de metilprednisolona con respuesta desfavorable. La carga viral resultó positiva para citomegalovirus (4019 copias de ADN) y recibió valganciclovir con evolución favorable en el seguimiento. Conclusiones: El síndrome de Evans asociado a infección por CMV es infrecuente. El tratamiento con valganciclovir podría ser beneficioso para cierto grupo de pacientes; sin embargo, hacen falta más estudios que demuestren la eficacia y seguridad de este tratamiento en este síndrome; más aún si está asociado a una elevada carga viral(AU)

Introduction: Evans syndrome is a rare autoimmune disorder, characterized by the descent of at least two blood cell lines. Publications of Evans syndrome and cytomegalovirus infection are scarce. Objective: To examine the case of a girl with Evans syndrome and active cytomegalovirus infection who responded favorably to antiviral therapy. Case presentation: A 13-month-old girl with a history of prematurity and low birth weight, who attended the consultation for presenting pallor and ecchymosis in the thorax, abdomen and extremities. Laboratory tests found thrombocytopenia and severe anemia after a positive direct Coombs test. She received pulses of methylprednisolone with unfavorable response. The viral load was positive for cytomegalovirus (4019 copies of DNA) and received valganciclovir with favorable evolution at follow-up. Conclusions: Evans syndrome associated with CMV infection is uncommon. Treatment with valganciclovir may be beneficial for a certain group of patients. However, more studies are needed to demonstrate the efficacy and safety of this treatment in this syndrome; even more so if it is associated with a high viral load(AU)

Sepsis por citomegalovirus en el paciente pediátrico / Cytomegalovirus Sepsis in the Pediatric Patient

Introducción: La infección severa por citomegalovirus resulta inusual en pacientes inmunocompetentes, sin embargo, cuando se presenta tiene una alta carga de morbilidad. Objetivo: Examinar el caso de un paciente nacido a término, con desnutrición aguda severa que presentó sepsis secundaria a una infección por citomegalovirus. Presentación del caso: Paciente de 2 meses y 7 días de edad que se llevó al servicio de urgencias por cuadro de un día de evolución de inapetencia, y fiebre. Sin antecedentes de prematurez o de infecciones oportunistas, y adecuado desarrollo para su edad. Se trasladó a un centro de mayor complejidad por deshidratación. En dicho centro el paciente presentó deterioro pulmonar con hallazgo de bronconeumonía, deterioro gastrointestinal por distensión severa de asas, deposiciones sanguinolentas, y deterioro hematológico por anemia hemolítica. Se descartó infección de origen bacteriano y fúngico, y se estableció que la etiología presentada se debía a citomegalovirus. Se trató con valganciclovir con una buena evolución clínica. Se discutió la fisiopatología, el diagnóstico, y tratamiento en relación con el caso presentado. Conclusiones: La infección grave por citomegalovirus en el periodo posnatal resultó muy rara, sin embargo, de presentar síntomas, son principalmente gastrointestinales o pulmonares; y ante la no respuesta al tratamiento convencional de enfermedades más comunes, se debe sospechar de manera oportuna una infección por este agente, dada la alta carga de morbilidad que produce(AU)

Introduction: Severe cytomegalovirus infection is unusual in immunocompetent patients; however, when it occurs it has a high burden of morbidity. Objective: To examine the case of a patient born at term who presented sepsis secondary to cytomegalovirus infection. Presentation of the case: A 2 months and 7 days old patient was taken to the emergency department for one day of evolution of inappetence and fever, with no history of prematurity or opportunistic infections and adequate development for his age. The patient was transferred to a more complex center due to dehydration, and in that center the patient presented pulmonary deterioration with bronchopneumonia, gastrointestinal deterioration due to severe distension of the loops, bloody stools, and hematologic deterioration due to hemolytic anemia. Bacterial and fungal infection was ruled out and the etiology was established as cytomegalovirus. She was treated with valganciclovir with a good clinical evolution. The pathophysiology, diagnosis and treatment are discussed in relation to the presented case. Conclusions: Severe cytomegalovirus infection in the postnatal period was very rare, however, if symptoms are present, they are mainly gastrointestinal or pulmonary; and in the absence of response to conventional treatment of more common diseases, an infection by this agent should be suspected in a timely manner, given the high burden of morbidity it produces(AU)

Changes in Valganciclovir Use Among Infants with Congenital Cytomegalovirus Diagnosis in the United States, 2009-2015 and 2016-2019.

From 2009-2015 to 2016-2019, the proportion of infants in the US with congenital cytomegalovirus treated with valganciclovir roughly doubled for infants enrolled with employer-sponsored insurance (from 16% to 29%) and Medicaid (from 16% to 36%). The proportion treated with valganciclovir increased for all congenital cytomegalovirus disease severity groups.

Obstructive cholangiopathy patient caused by cytomegalovirus and Kaposi sarcoma in a person living with HIV and hepatitis C.

We present the case of a 28-year-old man with recently-diagnosed human immunodeficiency virus and hepatitis C virus infection. He developed obstructive cholangiopathy secondary to cytomegalovirus and Kaposi sarcoma, both diagnosed by endoscopic retrograde cholangiopancreatography and biopsies. He received antiretroviral therapy, chemotherapy and valganciclovir with full recovery.

Valganciclovir Is Beneficial in Children with Congenital Cytomegalovirus and Isolated Hearing Loss.

OBJECTIVE: To evaluate the efficacy of antiviral treatment for infants with congenital cytomegalovirus (cCMV) with isolated sensorineural hearing loss (SNHL). STUDY DESIGN: Data were reviewed retrospectively for infants with isolated SNHL who received prolonged antiviral treatment between 2005 and 2017. Hearing status was evaluated for infants who had been followed for >1 year. RESULTS: Among 329 infants treated for cCMV, 59 (18%) were born with isolated SNHL. Hearing impairment was unilateral in 38 (64.4%) infants and bilateral in 21 (35.6%). Of the 80 affected ears at baseline, 55 (68.8%) improved, and only 2 (2.5%) deteriorated. Most of the improved ears (53/55 = 96.3%) returned to normal hearing with no deterioration observed in the ears that were unaffected at baseline. On best ear evaluation, of 21 infants who had bilateral hearing loss, 16 (76.1%) improved (93.7% regaining normal functional hearing); none deteriorated. CONCLUSION: Infants born with isolated SNHL due to cCMV were found to benefit from prolonged antiviral treatment. These children (and ears) showed significant improvement in hearing status and no deterioration of unaffected ears at baseline. Our data serve as observational evidence of the benefits of antiviral treatment in these children. Avoiding treatment of these children due to the lack of prospective data is debatable.

Incidencia y características clínicas de pacientes trasplantados renales con infección y enfermedad por citomegalovirus en un centro de trasplante / Incidence and clinical characteristics of renal transplanted patients with infection and disease by cytomegalovirus in a transplant center

Resumen Introducción: la infección viral más importante postrasplante renal es la infección por citomegalovirus (CMV), hay discrepancia entre centros y países en datos de incidencia de infección-enfermedad en esta población de pacientes. Diseño: se realiza un estudio observacional analítico, tomando una cohorte retrospectiva de pacientes mayores de 18 años, trasplantados renales de donante vivo o cadavérico entre el 2004 y 2015 con al menos seis meses de seguimiento. Material y métodos: se realiza muestreo no probabilístico por conveniencia, se toman los datos de las historias clínicas de los pacientes trasplantados renales, calculando la densidad de incidencia de infección-enfermedad por CMV y se describen las características clínicas y demográficas de los pacientes que presentaron estas patologías. Resultados: se analizaron 252 pacientes, encontrando 92.4% receptores con riesgo intermedio para CMV y 7.5% con riesgo alto, ninguno fue de riesgo bajo. Se identificaron 19 casos, 13 con infección (5.1%) y seis con enfermedad (2.3%). El compromiso gastrointestinal fue el más frecuente. El tiempo promedio desde el momento del trasplante hasta la aparición de la infección-enfermedad fue de 417 (±479) y 650 días (±481), respectivamente. La tasa de infección fue de 10.08 casos por 1000 pacientes/año y la tasa de enfermedad de 5.88 por 1000 pacientes/año. Conclusiones: la densidad de incidencia de infección-enfermedad por CMV en pacientes trasplantados renales fue de 10.08 casos y 5.88 casos por 1000 pacientes/año, respectivamente. Estas tasas son menores a las reportados en la literatura. Dada la baja frecuencia de eventos, no fue posible establecer factores de asociación.

Abstract Introduction: the most important viral infection after renal transplantation is cytomegalovirus (CMV) infection. There is a discrepancy between centers and countries in terms of incidence data of infection-disease in this population of patients. Design: an analytical observational study was conducted, taking a retrospective cohort of patients older than 18 years old, kidney transplant recipients of living or cadaveric donors between 2004 and 2015, with at least 6 months of follow-up. Material and methods: non-probability convenience sampling was done; data from the clinical records of the kidney transplant patients were taken, calculating the incidence density of CMV infection-disease and the clinical and demographic characteristics of the patients who presented these pathologies were described. Results: 252 patients were analyzed; 92.4% of recipients with intermediate risk for CMV and 7.5% with high risk were found. None of them had low risk. 19 cases were identified, 13 with infection (5.1%) and 6 with disease (2.3%). Gastrointestinal involvement was the most frequent. The average time from the time of transplant to the onset of the infection-disease was 417 (± 479) and 650 days (± 481), respectively. The infection rate was 10.08 cases per 1000 patients / year and the disease rate was 5.88 per 1000 patients/year. Conclusions: the incidence density of CMV infection-disease in renal transplant patients was 10.08 cases and 5.88 cases per 1000 patients / year, respectively. These rates are lower than those reported in the literature. Given the low frequency of events, it was not possible to establish association factors. (Acta Med Colomb 2018; 43: 20-23).

Cytomegalovirus-related transverse myelitis in an immunocompetent host: a subacute onset of an immune-mediated disease?

We report a case of transverse myelitis in an immunocompetent host with an atypical long onset of symptoms. A 56-year-old man was admitted to the hospital reporting 5 months of progressive ascending lower extremity weakness and numbness, inability to walk, bowel incontinence,urinary retention and several episodes of nausea and vomiting. MRI showed moderate spinal swelling and multiple hyperintense signal changes on cervical levels C2-C5 and thoracic levels T1-T3. Cerebrospinal fluid (CSF) showed pleocytosis and was positive for anti-cytomegalovirus (CMV) IgG intrathecal antibodies, but the CSF PCR for CMV was negative. The diagnosis of immune-mediated CMV-related transverse myelitis was established and the patient was treated with methylprednisolone and valgancyclovir. The patient had poor recovery and remained paraplegic at discharge.

Tolerability of up to 200 days of prophylaxis with valganciclovir oral solution and/or film-coated tablets in pediatric kidney transplant recipients at risk of cytomegalovirus disease.

This multicenter, open-label study evaluated the tolerability of extended prophylaxis with valganciclovir in pediatric kidney transplant recipients at risk of CMV disease. Fifty-six patients aged 4 months to 16 years received once-daily valganciclovir oral solution and/or tablets, dosed by BSA and renal function, for up to 200 days. The most common AEs on treatment were upper respiratory tract infection (33.9%), urinary tract infection (33.9%), diarrhea (32.1%), leukopenia (25.0%), neutropenia (23.2%), and headache (21.4%). There were fewer AEs during days 101-228 vs days 1-100. Twenty-seven patients (48.2%) had treatment-related AEs during valganciclovir treatment, most commonly leukopenia (21.4%), neutropenia (19.6%), anemia (7.1%), and tremor (5.4%). Treatment-related serious AEs were reported for nine patients (16.1%) and six withdrew due to AEs. Viremia was centrally confirmed in 10 patients; there was no confirmed CMV disease. One patient tested positive for a resistance mutation (UL97 L595F). Biopsy-proven acute rejection occurred in six patients (10.7%), but no graft loss or deaths occurred. In conclusion, up to 200 days of valganciclovir prophylaxis in pediatric kidney allograft recipients showed a safety profile consistent with that established in adult transplant patients.

Enfermedad por citomegalovirus en pacientes receptores de trasplante de corazón en un centro de referencia nacional / Cytomegalovirus disease in post-heart-transplant patients at a national reference center

Introduction: Heart transplantation remains as the treatment of choice when the heart failure is refractory to the medical or surgical therapy. Therefore, cytomegalovirus disease is an important post-heart-transplant infectious complication. Aims: To describe the prevalence and clinical characteristics of the cytomegalovirus disease after heart transplant surgery. Materials and Methods: A retrospective, descriptive study was conducted. It enrolled 35 heart-transplant patients attended in the Cardiovascular National Institute (INCOR), between 2010 and 2015. The information was obtained through the review of medical records. The demographic and relevant clinical variables were analyzed for the cytomegalovirus disease cases. Results: The population mean age was 39.49 ± 15.07 years and most of them were male patients (63%). The prevalence of the cytomegalovirus disease was 5.7% (two patients), both were seronegative for cytomegalovirus before transplantation. One of the patients had the disease before finishing the valganciclovir prophylaxis and the other after the end of it. Conclusion: The prevalence of the cytomegalovirus disease is slightly lower than in other studies. Moreover, the cytomegalovirus disease can remit with a prompt diagnosis and the proper medical treatment.

Introducción: El trasplante cardiaco es el tratamiento de elección ante la falla cardiaca refractaria a la terapia médica o quirúrgica. En base a ello, la enfermedad por citomegalovirus (CMV) es una importante complicación infecciosa post-trasplante de corazón. Objetivos: Describir la prevalencia y las características clínicas de los pacientes que desarrollaron enfermedad por CMV posttrasplante de corazón. Materiales y Métodos: Se realizó un estudio retrospectivo y descriptivo, donde se incluyó a los 35 pacientes que recibieron trasplante de corazón en el Instituto Nacional Cardiovascular entre el período 2010-2015. La información se obtuvo mediante la revisión de historias clínicas. Se analizaron las variables demográficas y clínicas relevantes de los casos con enfermedad por CMV. Resultados: La edad media de la población fue de 39,49 ± 15,07 años, siendo la mayoría de sexo masculino (63%). La prevalencia de la enfermedad por CMV fue de 5,7%, -dos pacientes-, ambos con serología negativa para CMV previa al trasplante. Uno de ellos presentó la enfermedad antes de terminar la profilaxis con valganciclovir y el otro luego del cese de la misma. Conclusión: La prevalencia de la enfermedad por CMV es ligeramente menor que en otros estudios. Asimismo, ésta puede remitir con un pronto diagnóstico y el adecuado tratamiento médico.

[Cytomegalovirus disease in post-heart-transplant patients at a national reference center]. / Enfermedad por citomegalovirus en pacientes receptores de trasplante de corazón en un centro de referencia nacional.

INTRODUCTION: Heart transplantation remains as the treatment of choice when the heart failure is refractory to the medical or surgical therapy. Therefore, cytomegalovirus disease is an important post-heart-transplant infectious complication. AIMS: To describe the prevalence and clinical characteristics of the cytomegalovirus disease after heart transplant surgery. MATERIALS AND METHODS: A retrospective, descriptive study was conducted. It enrolled 35 heart-transplant patients attended in the Cardiovascular National Institute (INCOR), between 2010 and 2015. The information was obtained through the review of medical records. The demographic and relevant clinical variables were analyzed for the cytomegalovirus disease cases. RESULTS: The population mean age was 39.49 ± 15.07 years and most of them were male patients (63%). The prevalence of the cytomegalovirus disease was 5.7% (two patients), both were seronegative for cytomegalovirus before transplantation. One of the patients had the disease before finishing the valganciclovir prophylaxis and the other after the end of it. CONCLUSION: The prevalence of the cytomegalovirus disease is slightly lower than in other studies. Moreover, the cytomegalovirus disease can remit with a prompt diagnosis and the proper medical treatment.

Evaluation of Low- Versus High-dose Valganciclovir for Prevention of Cytomegalovirus Disease in High-risk Renal Transplant Recipients.

BACKGROUND: Despite proven efficacy of prolonged cytomegalovirus (CMV) prophylaxis using valganciclovir 900 mg/day, some centers use 450 mg/day due to reported success and cost savings. This multicenter, retrospective study compared the efficacy and safety of 6 months of low-dose versus high-dose valganciclovir prophylaxis in high-risk, donor-positive/recipient-negative, renal transplant recipients (RTR). METHODS: Two hundred thirty-seven high-risk RTR (low-dose group = valganciclovir 450 mg/day [n = 130]; high-dose group = valganciclovir 900 mg/day [n = s7]) were evaluated for 1-year CMV disease prevalence. Breakthrough CMV, resistant CMV, biopsy-proven acute rejection (BPAR), graft loss, opportunistic infections (OI), new-onset diabetes after transplantation (NODAT), premature valganciclovir discontinuation, renal function and myelosuppression were also assessed. RESULTS: Patient demographics and transplant characteristics were comparable. Induction and maintenance immunosuppression were similar, except for more early steroid withdrawal in the high-dose group. Similar proportions of patients developed CMV disease (14.6% vs 24.3%; P = 0.068); however, controlling CMV risk factor differences through multivariate logistic regression revealed significantly lower CMV disease in the low-dose group (P = 0.02; odds ratio, 0.432, 95% confidence interval, 0.211-0.887). Breakthrough and resistant CMV occurred at similar frequencies. There was no difference in renal function or rates of biopsy-proven acute rejection, graft loss, opportunistic infections, or new-onset diabetes after transplantation. The high-dose group had significantly lower mean white blood cell counts at months 5 and 6; however, premature valganciclovir discontinuation rates were similar. CONCLUSIONS: Low-dose and high-dose valganciclovir regimens provide similar efficacy in preventing CMV disease in high-risk RTR, with a reduced incidence of leukopenia associated with the low-dose regimen and no difference in resistant CMV. Low-dose valganciclovir may provide a significant cost avoidance benefit.

The role of secondary cytomegalovirus prophylaxis for kidney and liver transplant recipients.

BACKGROUND: The role of secondary cytomegalovirus (CMV) prophylaxis, defined as the continuation of valganciclovir to prevent relapse after the successful treatment of CMV disease, is not well understood. METHODS: Cases of CMV disease in patients who underwent kidney or liver transplantation from January 2001 to January 2010 were reviewed to determine if the use of secondary prophylaxis was associated with fewer relapses or other favorable outcomes. Secondary prophylaxis was used at the discretion of each treating clinician, without an institutional protocol. RESULTS: Twenty-two cases of CMV disease in kidney transplant recipients and 20 cases in liver transplant recipients were included. Relapsed CMV disease was significantly more common among kidney transplant recipients (5/22 vs. 0/20, P = 0.049). Of 22 kidney transplant recipients, 16 received secondary prophylaxis. After a mean of 3.7 years, relapsed CMV disease occurred in three of 16 patients who received secondary prophylaxis and in two of six who did not. Among liver transplant recipients, only two of 20 patients received secondary prophylaxis. After a mean of 3.2 years, no relapsed CMV disease occurred. The use of secondary prophylaxis was not significantly associated with fewer episodes of CMV relapse, graft loss, or death. Time to clearance of CMV viremia during treatment was significantly longer in those who relapsed (mean, 30 days vs. 20 days; P = 0.037). CONCLUSION: These findings suggest that secondary CMV prophylaxis may not provide additional benefit after the successful treatment of CMV disease, particularly among liver transplant recipients.

Valganciclovir: prevención y tratamiento de infecciones por CMV en pacientes trasplantados / Valganciclovir: prevention and treatment of CMV infections in transplant patients

INTRODUCCIÓN: Existen varios estudios clínicos, detallados con anterioridad, que demostraron que valganciclovir v.o. es igual de efectivo que ganciclovir en la prevención de enfermedad por CMV en pacientes trasplantados de alto riesgo. También demostró tener un perfil de seguridade similar con una clara conveniencia en pacientes que pueden recibir tratamiento ambulatorio. La diferencia de costos podría ser compensada por la disminución en los gastos por internación y complicaciones asociadas. Por lo tanto, consideramos que valganciclovir v.o. es una alternativa adecuada y costo-efectiva para la prevención de enfermedad por CMV en pacientes trasplantados de alto riesgo. EVALUACIÓN DE LA SEGURIDAD: Valganciclovir es un profármaco, droga precursora del Ganciclovir, y por consiguiente cabe esperar que los efectos adversos observados con Valganciclovir sean similares, cualitativamente y cuantitativamente, a los asociados al Ganciclovir. De hecho todos los eventos adversos observados en los estudios frente a la administración de Valganciclovir ya se habían detectado con el Ganciclovir. DISCUSIÓN: Este estudio muestra una mayor eficacia del tratamiento anticipado en comparación a la profilaxis antiviral, en cuanto a la variable de supervivencia del injerto en pacientes con trasplante renal. Sin embargo, estos resultados no son del todo confiables ya que el estudio presenta varias limitaciones metodológicas. En primer lugar, este estudio no fue diseñado con el objetivo de analizar la supervivencia del injerto. Por otro lado, la muestra estudiada es pequeña y la proporción de pacientes con alto riesgo (D+/R-) de desarrollo de enfermedad por CMV que incorpora en el análisis es menor del 20% del total estudiado (12%, n=4) en el caso de la profilaxis y un 17% (n=6) en el grupo preventivo). Finalmente, existen varios estudios previos cuyos resultados son contradictorios con los de este estudio. CONCLUSIONES: Eficacia: Existe evidencia de que valganciclovir vía oral tiene una eficacia similar a ganciclovir endovenoso en la profilaxis de enfermedad por CMV en pacientes con transplante de órganos sólidos de alto riesgo. Seguridad: Ganciclovir y valganciclovir presentan un perfil de seguridad similar. Sin embargo, valganciclovir se ha asociado a una mayor incidencia de eventos adversos hematológicos (principalmente leucopenia y neutropenia). Por esta razón no se recomenda su uso en pacientes que presenten recuentos de neutrófilos menor a 500 cel. /ml, recuento de plaquetas es <25,000/ micro litro ó pacientes con una concentración de Hb <8 g/dl. Conveniencia: Valganciclovir tiene la ventaja de ser administrado por vía oral y en una sola toma diaria, mientras que ganciclovir se administra sólo por vía endovenosa. El uso de valganciclovir permite el tratamiento ambulatorio de pacientes trasplantados. Si bien no se encuentran mayores beneficios clínicos en comparación con el uso de ganciclovir por vía oral, sólo existe valganciclovir disponible por esta vía en nuestro país. Costo: el análisis comparativo de costos entre valganciclovir vo y ganciclovir ev, en la profilaxis de enfermedad por CMV, muestra una diferencia de $ 12840 a favor de ganciclovir. Proponemos la inclusión del valganciclovir al formulario terapéutico del Hospital.