Comparative Emergence of Maribavir and Ganciclovir Resistance in a Randomized Phase 3 Clinical Trial for Treatment of Cytomegalovirus Infection.

BACKGROUND: Among 547 patients receiving maribavir or valganciclovir for first-episode cytomegalovirus infection after hematopoietic cell transplant, the treatment response rate was 69.6% and 77.4% respectively. Development of maribavir and ganciclovir resistance was compared after receiving either drug. METHODS: Viral mutations conferring drug resistance were analyzed in plasma DNA extracts at baseline and post-treatment. RESULTS: Prior antiviral drug exposure was limited, with only 2 instances of baseline drug resistance detected. An equal number (n=241) received valganciclovir or maribavir for at least 21 days (median 55-56 days). Among them, drug resistance mutations were detected in 24 (10%) maribavir recipients at 35-125 days (median 56) after starting therapy, including in 12 of 14 who experienced a viral load rebound while on therapy. Ganciclovir resistance mutations developed in 6 (2.5%) valganciclovir recipients at 66-110 days (median 90). One maribavir recipient developed a novel UL97 gene mutation (P-loop substitution G343A) that conferred strong maribavir and ganciclovir resistance in vitro. Viral clearance was confirmed in 17 (74%) of 23 patients with emergent maribavir resistance after re-treatment with an alternative CMV antiviral drug. CONCLUSION: After 3-8 weeks of therapy, maribavir resistance emerged earlier and more frequently than ganciclovir resistance but was usually treatable using alternative therapy. CLINICAL TRIALS REGISTRATION: NCT02927067 (AURORA).

Efficacy and Safety of Valganciclovir in Congenital Cytomegalovirus Infection with Isolated Intrahepatic Cholestasis: A Randomized Controlled Trial.

Purpose: Cytomegalovirus (CMV) infection affects the hepatic, neurologic, hematopoietic, respiratory, gastrointestinal, and other organs, resulting in a high mortality rate and long-term sequelae. It may cause acute or chronic hepatitis, or even lead to hepatic cirrhosis. Valganciclovir (VGCV) is an effective, safe, and well-tolerated treatment for congenital CMV infection, without any serious adverse effects. This study was conducted to evaluate the clinical, biochemical, and virological profiles of infants with CMV with intrahepatic cholestasis and to determine the outcomes with or without treatment with VGCV. Methods: Twenty infants aged <6 months diagnosed with congenital CMV infection with evidence of intrahepatic cholestasis were included in this study. Randomization was used to divide the study participants into 2 groups. The control group (n=10) was treated with only supportive management, and the intervention group (n=10) was treated with oral VGCV at 16 mg/kg/dose 12 hours a day for 6 weeks plus supportive treatments. Physical examinations and biochemical, serological, and virological tests were performed at the time of diagnosis and at the end of 6 weeks and 6 months. Results: The control and intervention groups were compared in terms of clinical and laboratory parameters such as jaundice, dark urine, pale stool, hepatomegaly, total bilirubin, aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, and CMV polymerase chain reaction load, which showed a significant reduction after treatment in the intervention group (p<0.05) with oral VGCV, with very few side effects, whereas the control group showed no significant changes. Conclusion: Oral VGCV can be used to effectively treat CMV infection with intrahepatic cholestasis without notable side effects.

High malignancy rate in the absence of viral prophylaxis after kidney transplantation in Sudan.

BACKGROUND: Kidney transplantation in Sudan is funded by the government. Cytomegalovirus prophylaxis is provided for patients who receive biological induction or have recipient-negative donor-positive cytomegalovirus serology. Doctor Selma Center for Kidney Diseases joined the national kidney transplant program in May 2019. Since then, we observed the frequent occurrence of cancer in patients who received modest immunosuppression without viral prophylaxis. METHODS: We retrospectively divided kidney transplant recipients between 2019 and 2021 into two groups according to cytomegalovirus prophylaxis and compared tumor occurrence rates. RESULTS: The first group included 77 patients who did not receive biological induction or cytomegalovirus prophylaxis. The second group included 92 patients who received valganciclovir for 3-6 months. There was no other antiviral treatment except entecavir for chronic hepatitis B virus infection in eight patients. Five patients in the first group developed malignancy. The first patient presented eight months post-transplant with Kaposi sarcoma of the stomach and responded to treatment with sirolimus. The second patient presented nine months post-transplant with cutaneous Kaposi sarcoma and also responded to sirolimus. Two patients presented two and four months post-transplant with aggressive non-cutaneous Kaposi sarcoma that involved the gastrointestinal tract and lymphatic system and died soon afterwards. The fifth patient presented three years post-transplant with non-Hodgkin lymphoma of the duodenum and is currently receiving chemotherapy. Malignancy rate (6.5% vs 0.0%, P = 0.02) and Kaposi sarcoma rate (5.2% vs 0.0%, P = 0.04) were significantly higher in the first group. CONCLUSION: In Sudan, omitting valganciclovir prophylaxis after kidney transplantation was associated with a high rate of virus-induced malignancy.

Comparison of valganciclovir versus foscarnet for the treatment of cytomegalovirus viremia in adult acute leukemia patients after allogeneic hematopoietic cell transplantation.

Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult acute leukemia (AL) patients suffered allo-HCT between 2017 and 2021, who developed CMV viremia post-HCT and treated with valganciclovir or foscarnet, to evaluate effectiveness and safety of both drugs. Viremia clearance rates (14 and 21 d post treatment) and toxicities were similar in two groups. However, valganciclovir was associated with a lower cumulative incidence of CMV recurrence within 180 days (16.7% vs. 35.7%, p=0.029) post CMV clearance. Finally, 2-year TRM was lower in valganciclovir group (9.7% ± 0.2% vs. 26.2% ± 0.3%, p = 0.026), result a superior 2-year overall survival (OS; 88.1% ± 5.2% vs. 64.4% ± 5.5%, p = 0.005) and leukemia-free survival (LFS; 82.0% ± 5.9% vs. 58.9% ± 5.6%, p = 0.009). Valganciclovir might decrease CMV viremia recurrence and led to better long-term outcome than foscarnet in adult AL patients developed CMV viremia post-HCT. Considering the inherent biases of retrospective study, well-designed trials are warranted to validate our conclusion.

Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir.

BACKGROUND: Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir. METHODS: In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%). CONCLUSIONS: Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA].

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.

Ganciclovir as a potential treatment for glioma: a systematic review and meta-analysis.

BACKGROUND: Glioma is a challenging malignant tumor with a low survival rate and no effective treatment. Recently, ganciclovir, an antiviral drug, combined with gene therapy and its own antiviral ability, has been proposed as a potential treatment for glioma. However, there are differences in the results of various clinical trials. In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy of ganciclovir in treating glioma. METHODS: We searched databases such as PubMed, EMBASE, and Cochrane Library before March 30, 2023. The search terms included glioma, ganciclovir, valganciclovir and treatment. Calculated 1, 2 and 4-year survival rate by risk difference (RD), and overall survival (OS) by odds ratio (OR). RESULTS: Five randomized controlled trials (RCTs) with a total of 606 high-grade glioma patients were included. The results showed that ganciclovir can improve 2-yeaer (RD = 0.179, 95% CI 0.012-0.346, P = 0.036) and 4-year survival rate (RD = 0.185, 95% CI 0.069-0.3, P = 0.002) and OS (OR 2.393, 95% CI 1.212-4.728, P = 0.012) compared with the control group. CONCLUSIONS: This meta-analysis showed that ganciclovir significantly improved the prognosis of glioma patients. Therefore, we suggest that more cases of ganciclovir as a glioma treatment can be conducted, or a large clinical trial can be designed.

The Multifaceted Clinical Characteristics of Congenital Cytomegalovirus Infection: From Pregnancy to Long-Term Outcomes.

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.

Cytomegalovirus Infection Post-Allogeneic Stem Cell Transplantation: Experience from a Country with High Seropositivity.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Limited data are available from developing countries regarding the frequency of CMV infection and treatment outcomes. We enrolled 230 consecutive patients undergoing allogeneic HSCT for various hematologic disorders at the Armed Forces Bone Marrow Transplant Center/National Institute of Blood And Marrow Transplant between February 2017 and December 202. CMV reactivation post-HSCT was monitored weekly starting at day +30 and continuing until day +100, and preemptive antiviral therapy was administered to prevent CMV disease in all HSCT recipients with ≥2000 CMV copies/mL. The median age of the study cohort was 9.5 years (range, .6 to 53 years), and the male:female ratio was 2.4:1. The most frequent indication for HSCT was beta thalassemia major (36.1%), followed by aplastic anemia (23.9%). Malignant disorders constituted 20% of all the patients. Pretransplantation CMV seropositivity was 99.1% for the recipients and 99.5% for the donors. CMV infection was seen in 66.1% of the patients, and the median time to CMV DNAemia was 36 days (range, 12 to 95 days). Preemptive antiviral therapy was administered to 140 patients with a CMV viral load ≥2000 copies/mL (61%). In multivariate analysis, patient age >12 years, steroid administration, and use of mycophenolate mofetil with or without post-transplantation cyclophosphamide was associated with the greatest probability of CMV reactivation. Overall survival was 97.4% in patients without CMV reactivation, compared to 80.3% in those with CMV reactivation (P = .001). Event-free survival was 78.7% in the total study cohort, including 89.7% for patients without CMV reactivation and 73% for patients with CMV reactivation (P = .003). Our study is the first from this region to explore the frequency of CMV seropositivity and CMV infection, risk factors for CMV reactivation, and outcomes of antiviral therapy in HSCT recipients.

Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Treatment of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (alloHCT) patients with ganciclovir is complicated by toxicity and resistance. This study aimed to develop an intravenous ganciclovir population pharmacokinetic model for post-alloHCT patients and to determine dosing regimens likely to achieve suggested therapeutic exposure targets. We performed a prospective observational single-center pharmacokinetic study in adult alloHCT patients requiring treatment with intravenous ganciclovir for CMV viremia or disease. Samples were analyzed using a validated ultraperformance liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. Twenty patients aged 18 to 69 years were included in the study. A 2-compartment model with linear elimination from the central compartment and between occasion variability best described the data. Incorporating creatinine clearance (CLCR) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and presence of continuous renal replacement therapy as covariates for ganciclovir clearance improved the model. Compared to current dosing recommendations, simulations demonstrated loading doses were required to achieve a target AUC24 of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CLCR is required to achieve the suggested exposures for efficacy (AUC24 >80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC24 <120/<60 mg.h/L for induction/maintenance). Intravenous ganciclovir dosing in alloHCT patients can be guided by CLCR estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.

Incidence and antiviral treatment of cytomegalovirus infection in infants with biliary atresia.

PURPOSE: Patients with biliary atresia (BA) and cytomegalovirus (CMV) infection may have poorer outcomes after Kasai portoenterostomy (KPE) than uninfected patients, suggesting a rationale for antiviral treatment (AVT). We aimed to describe the incidence of CMV infection and of AVT in BA patients, and to detect any differences between infected and uninfected patients to conclude if AVT is of use. METHODS: Data on BA patients who underwent KPE 2004-2020 were retrospectively collected, and the outcome was analyzed with regard to CMV status. RESULTS: Fifteen out of forty-six (33%) BA patients had signs of ongoing CMV infection. They did not differ significantly from the CMV-negative patients regarding rate of prematurity, birth weight, or biochemical markers but were slightly older at KPE. All patients received steroids postoperatively and all patients with ongoing CMV infection received AVT with very good effect on viremia and without major side effects. The AVT consisted of oral valganciclovir (10-40 (- 58) mg/kg/d) or intravenous ganciclovir (5.3-11 mg/kg/d). CONCLUSION: Ongoing CMV infection is common in this group of patients. The viremia can effectively be treated with AVT without any major side effects. Larger, randomized studies are needed to clarify the possible effect on clinical outcome.

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)

Perinatal Cytomegalovirus Infection.

Purpose of review: There have been recent advances in the field of congenital CMV infection (cCMV) related to antiviral treatment of pregnant women and infants, the implementation of newborn CMV screening programs, and the frequency and diagnosis of complications among infected children. In addition, postnatal CMV infection (pCMV) is increasingly recognized as a potential cause of long-term sequelae in addition to acute complications among preterm infants, raising important questions related to treatment, and prevention. Recent findings: High-dose valacyclovir appears to be safe and effective for the prevention of cCMV among women with first-trimester primary CMV infection. New studies reveal high rates of vestibular dysfunction and neuropsychiatric manifestations among children with cCMV. Some studies report associations between pCMV and long-term consequences, including neurodevelopmental delay and bronchopulmonary dysplasia, among very low birth weight infants, in addition to high risk of sepsis and death acutely, which has motivated efforts to eliminate the virus from breast milk by different methods. Summary: More long-term complications of cCMV are increasingly recognized among children previously thought to be asymptomatic. Although a preventive CMV vaccine may be achievable, strategies to reduce the burden of cCMV disease include maternal education about risk-reduction behaviors, antiviral treatment of pregnant women with primary infection, and newborn screening to allow timely, appropriate care. Similarly, although it remains unclear if pCMV causes long-term problems, there is growing interest in identifying and preventing disease from CMV infections among preterm infants.

Oral valganciclovir in human immunodeficiency virus-positive patients suffering from cytomegalovirus retinitis at a tertiary care hospital in North India.

Purpose: To study clinical efficacy of valganciclovir in cytomegalovirus retinitis (CMVR) in human immunodeficiency virus (HIV)-positive-positive patients in a tertiary care clinic in a developing nation. Methods: In a retrospective study, systemic and ocular records of HIV patients suffering from CMVR and treated with valganciclovir, were analyzed. Primary outcome measures were involvement of the other eye, incidence of retinal detachment, systemic involvement, and mortality encountered. Secondary outcome measures included change in BCVA. Results: Out of nine patients who were included, two patients developed CMVR in the other eye and only one patient (11.11%) developed retinal detachment during the course of the study. No patient developed any systemic manifestations or had mortality during the course of the study. The change in BCVA was not statistically significant. Conclusion: Use of oral valganciclovir showed good outcome and was found to be a better alternative compared to the use of intravitreal ganciclovir in the literature. Introduction of valganciclovir at an affordable price in developing nations can decrease disease burden.

Commentary: Development of Therapeutics for Congenital Cytomegalovirus Infection.

In the mid 1980's, I flew from Birmingham, Alabama to San Francisco, rented a car, and drove to Palo Alto so that I could meet with John Martin at Syntex. John, along with Julian Verheyden, synthesized ganciclovir, which had significant in vitro activity against cytomegalovirus (CMV) in vitro. This drug provided my colleagues and me an opportunity to evaluate it as a therapeutic agent for congenital CMV infection, knowing full well that it was mutagenic, teratogenic, and carcinogenic. John in his wisdom convinced the management of Syntex to provide ganciclovir for this disease, allowing me to study this drug in symptomatic congenitally infected children through the NIAID Collaborative Antiviral Study Group (CASG). Certainly, no other person or company would advocate for the use of such a medication in children, regardless of disease severity, because of its toxicity profile. Since these early days, ganciclovir, and subsequently its prodrug valganciclovir, have become the standard of care for the treatment of congenital cytomegalovirus infection. The following commentary defines the need and progress in the development of therapy.

Valganciclovir as Add-on to Second-Line Therapy in Patients with Recurrent Glioblastoma.

Glioblastoma invariably recurs despite aggressive and multimodal first-line treatment and no standardized second-line therapy exists. We previously reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged overall survival in 102 patients with newly diagnosed glioblastoma compared to contemporary controls. Here we present the results of retrospective survival analyses including patients with glioblastoma that initiated valganciclovir therapy after recurrence. Twenty-nine patients with recurrent glioblastoma received valganciclovir as an add-on to second-line therapy at Karolinska University Hospital. Contemporary controls were 109 patients with glioblastoma who received similar second-line therapy at our institution. We retrospectively analyzed survival data of these patients. Patients with recurrent glioblastoma who received valganciclovir had longer median overall survival after recurrence than controls (12.1 vs. 7.4 months, respectively, p = 0.0028). The drug was well tolerated. Both patients who underwent re-operation and patients that were not re-operated after recurrence benefitted significantly from valganciclovir therapy. Valganciclovir prolonged survival after recurrence both in patients with an unmethylated and methylated MGMT promoter gene. Valganciclovir was safe to use and prolonged median survival after recurrence for patients with recurrent glioblastoma, re-operated or not after recurrence, and with methylated or unmethylated MGMT promoter gene.

Efficacy and Safety of Antiviral Agents in Preventing Allograft Rejection Following CMV Prophylaxis in High-Risk Kidney Transplantation: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Many antiviral agents have been studied in clinical trials for allograft rejection prevention following cytomegalovirus (CMV) prophylaxis in high-risk kidney transplant patients. However, data on the most effective and safest treatment are lacking. We conducted a systematic review and network meta-analysis to rank CMV prophylaxis agents for allograft rejection prevention following CMV prophylaxis in high-risk kidney transplant patients according to their efficacy and safety. We conducted searches on the MEDLINE, Embase, SCOPUS, and CENTRAL databases, as well as the reference lists of selected studies up to December 2021, for published and peer-reviewed randomized controlled trials assessing the efficacy of CMV prophylaxis agents in high-risk kidney transplant patients. Thirteen studies were independently selected by three reviewers and included post-kidney transplant patients indicated for CMV prophylaxis who had been randomized to receive prophylactic antiviral agents or standard of care. The reviewers independently extracted data from the included studies, and direct and network meta-analyses were applied to assess the study outcomes. The probability of efficacy and safety was evaluated, and the drugs were assigned a numerical ranking. We evaluated the risk of bias using the Cochrane Risk of Bias 2.0 tool. The primary outcome was an incidence of biopsy-proven acute rejection, whereas the secondary outcome was a composite of major adverse drug reactions. Each outcome referred to the definition provided in the original studies. Valganciclovir, valacyclovir, and ganciclovir were identified to significantly decrease the incidence of biopsy-proven acute rejection with pooled risk differences (RDs) of -20.53% (95% confidence interval [CI] = -36.09% to -4.98%), -19.3% (95% CI = -32.7% to -5.93%), and -10.4% (95% CI = -19.7% to -0.12%), respectively. The overall major adverse drug reaction was 5.7% without a significant difference when compared with placebo. Valganciclovir had the best combined efficacy and safety among the examined antiviral agents and was the most effective and safest antiviral agent overall for allograft rejection prevention following CMV prophylaxis. Valacyclovir was the optimal alternative antiviral agent for patients who were unable to tolerate intravenous ganciclovir or access oral valganciclovir as financial problem. However, compliance and dose-related toxicities should be closely monitored.

Cytomegalovirus colitis in a child with leukemia: a case report.

A 17-month-old boy with a known case of T-cell acute lymphoblastic leukemia was admitted to the authors' hospital because of blood-streaked diarrhea a week after his last chemotherapy session. Initially, he was treated with supportive care and an empiric regimen for opportunistic causes of diarrhea; however, this was not effective. Eventually, evaluation of his stool with PCR showed positivity for cytomegalovirus. Consequently, he responded dramatically to treatment with ganciclovir. Although cytomegalovirus colitis is rare, a few case reports suggest cytomegalovirus as a possible cause of colitis in children with leukemia, which can be fatal and should be considered as a differential diagnosis.

A comparative study of valaciclovir, valganciclovir, and artesunate efficacy in reactivated HHV-6 and HHV-7 infections associated with chronic fatigue syndrome/myalgic encephalomyelitis.

This study aimed to compare the efficacy of valaciclovir, valganciclovir, and artesunate in treating chronic reactivated human herpesvirus type 6 (HHV-6) and human herpesvirus type 7 (HHV-7) infection associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). From 255 patients (192 cases) with reactivated HHV-6 and HHV-7 infections (confirmed based on blood leukocyte PCR), valaciclovir, valganciclovir, or artesunate was administered at a dose of 3000, 900, and 100 mg/day, respectively, for 3 months (study group). The control group consisted of similar patients with ME/CFS (n = 63) not taking any antiviral drugs. The significance of differences was evaluated by Student's t-test and the nonparametric criterion-the number of Z-signs. Negative PCR results in patients with HHV-6 and HHV-7 treated with valaciclovir was achieved in 26% and 23% (first month), 34%, and 28% (second month), 37% and 34% of cases (third month), respectively (P < 0.05; Z < Z0.05 ). The same results with valganciclovir were obtained in 35% and 33% (first month), 44% and 39% (second month), 48% and 45% of cases (third month), but with artesunate in 44% and 41% (first month), 57% and 53% (second month), 68% and 63% of cases (third month), respectively (P < 0.05; Z < Z0.05 ). Artesunate is more effective than valganciclovir and valacyclovir in patients with ME/CFS with reactivated HHV-6 and HHV-7 infections.

Human Cytomegalovirus-Specific T-Cell Reconstitution and Late-Onset Cytomegalovirus Infection in Hematopoietic Stem Cell Transplantation Recipients following Letermovir Prophylaxis.

Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n = 30; LTV group) and those receiving preemptive therapy (n = 31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P = .434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P = .232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P = .024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P = .124) and a higher rate of acute GVHD grade III-IV (P = .103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.