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1.
Clin Lab ; 70(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38868867

RESUMO

BACKGROUND: Both humoral and cell-mediated immunity of the patient affected by multiple myeloma (MM) are impaired; thus, infection is the main cause of the onset of symptoms and death caused by MM. Bortezomib is a first-line drug approved for patients with multiple myeloma (MM) and has significantly increased their overall survival. However, bortezomib-induced peripheral neuropathy (PN) remains a significant side effect that has led to its discontinuation in some patients. Guillain-Barre syndrome (GBS) is thought to be related to immune damage, and most patients have cytomegalovirus (CMV), Epstein-Barr virus (EBV), or mycoplasma infection before onset. Cases of GBS secondary to MM are rare. METHODS: We provide a case of GBS caused by cytomegalovirus infection after MM treatment, and briefly review the existing literature. RESULTS: Secondary GBS after MM. This patient received active treatment. The clinical symptoms are gradually improving. CONCLUSIONS: The use of bortezomib has the risk of reactivating the virus. It is more about the reactivation of hep-atitis B virus. Nonetheless, cytomegalovirus and Epstein-Barr virus shall have our attention. Patients with MM need to monitor CMV, regularly, especially during the treatment of bortezomib. At the same time, they also need to closely monitor the symptoms and signs of the nervous system to guard against the occurrence of GBS.


Assuntos
Bortezomib , Infecções por Citomegalovirus , Síndrome de Guillain-Barré , Mieloma Múltiplo , Feminino , Humanos , Pessoa de Meia-Idade , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Bortezomib/efeitos adversos , Citomegalovirus/imunologia , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/virologia , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/etiologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/complicações
2.
Transpl Infect Dis ; 26(3): e14282, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38824435

RESUMO

OBJECTIVES: Prophylaxis (P) or pre-emptive strategy (PS) in high-risk liver transplant recipients (LTRs) are either recommended. We compared the results of each strategy. METHODS: Two groups of LTR transplanted during two consecutive periods were compared. Only cytomegalovirus (CMV)-mismatched LTR (Donor +/ Recipient -) were included. The primary endpoints were: the onset of polymerase chain reaction-based DNAemia and the proportion of patients with CMV disease. A number of episodes of CMV infection, antiviral therapy, ganciclovir resistance, infectious or immunological complications, cost of both strategies, and survival (1, 5, and 10 years) were also compared. RESULTS: Forty-eight and 60 patients were respectively included in the P and PS groups. Eighteen (38%) in the P group and 56 (93%) in the PS group had CMV DNAemia (p <.0001) with a similar CMV disease rate (16.7% and 15%). Duration of curative therapy was longer in the PS group: 91 days versus 16 (p <.0001). Acute rejection was less frequent (p = .04) and more patients experienced a ganciclovir-resistant CMV infection in the PS group (10% vs. 0, p = .03). The drug-associated cost of PS was higher (10 004 vs. 4804€) and the median number of rehospitalization days tended to be higher (6 vs. 4, p = .06). Survival at any time was similar. CONCLUSION: We reported more CMV DNAemias and ganciclovir-resistant CMV events with PS. The cost of the PS strategy was higher.


Assuntos
Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Ganciclovir , Transplante de Fígado , Humanos , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/virologia , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Feminino , Citomegalovirus/efeitos dos fármacos , Ganciclovir/uso terapêutico , Ganciclovir/administração & dosagem , Adulto , Idoso , Transplantados/estatística & dados numéricos , DNA Viral/sangue , Rejeição de Enxerto/prevenção & controle , Estudos Retrospectivos , Farmacorresistência Viral
3.
Transpl Infect Dis ; 26(3): e14279, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38742601

RESUMO

BACKGROUND: Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. METHODS: This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. RESULTS: A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p = .370). The median (interquartile range) white blood cell (WBC) count was 3.1 (2.1-5.6) at LET initiation which increased to 5.1 (3.9-7.2) at the end of follow-up (p <.001). For VGCV controls, WBC was 4.8 (3.4-7.2) at baseline and 5.4 (3.6-7.2) at the end of follow-up; this difference was not statistically significant (p = .395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). CONCLUSION: LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.


Assuntos
Acetatos , Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Transplante de Pulmão , Transplantados , Valganciclovir , Humanos , Transplante de Pulmão/efeitos adversos , Infecções por Citomegalovirus/prevenção & controle , Masculino , Valganciclovir/uso terapêutico , Valganciclovir/administração & dosagem , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Antivirais/administração & dosagem , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Citomegalovirus/efeitos dos fármacos , Adulto , Acetatos/uso terapêutico , Acetatos/efeitos adversos , Acetatos/administração & dosagem , Quinazolinas/uso terapêutico , Quinazolinas/efeitos adversos , Quinazolinas/administração & dosagem , Resultado do Tratamento , Idoso
5.
PLoS One ; 19(5): e0303995, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38771836

RESUMO

BACKGROUNDS: In critically ill patients with COVID-19, secondary infections are potentially life-threatening complications. This study aimed to determine the prevalence, clinical characteristics, and risk factors of CMV reactivation among critically ill immunocompetent patients with COVID-19 pneumonia. METHODS: A retrospective cohort study was conducted among adult patients who were admitted to ICU and screened for quantitative real-time PCR for CMV viral load in a tertiary-care hospital during the third wave of the COVID-19 outbreak in Thailand. Cox regression models were used to identify significant risk factors for developing CMV reactivation. RESULTS: A total of 185 patients were studied; 133 patients (71.9%) in the non-CMV group and 52 patients (28.1%) in the CMV group. Of all, the mean age was 64.7±13.3 years and 101 patients (54.6%) were males. The CMV group had received a significantly higher median cumulative dose of corticosteroids than the non-CMV group (301 vs 177 mg of dexamethasone, p<0.001). Other modalities of treatments for COVID-19 including anti-viral drugs, anti-cytokine drugs and hemoperfusion were not different between the two groups (p>0.05). The 90-day mortality rate for all patients was 29.1%, with a significant difference between the CMV group and the non-CMV group (42.3% vs. 24.1%, p = 0.014). Median length of stay was longer in the CMV group than non-CMV group (43 vs 24 days, p<0.001). The CMV group has detectable CMV DNA load with a median [IQR] of 4,977 [1,365-14,742] IU/mL and 24,570 [3,703-106,642] in plasma and bronchoalveolar fluid, respectively. In multivariate analysis, only a cumulative corticosteroids dose of dexamethasone ≥250 mg (HR = 2.042; 95%CI, 1.130-3.688; p = 0.018) was associated with developing CMV reactivation. CONCLUSION: In critically ill COVID-19 patients, CMV reactivation is frequent and a high cumulative corticosteroids dose is a significant risk factor for CMV reactivation, which is associated with poor outcomes. Further prospective studies are warranted to determine optimal management.


Assuntos
COVID-19 , Estado Terminal , Infecções por Citomegalovirus , Citomegalovirus , Humanos , Masculino , Pessoa de Meia-Idade , COVID-19/epidemiologia , COVID-19/virologia , COVID-19/complicações , Feminino , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/complicações , Fatores de Risco , Idoso , Citomegalovirus/fisiologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/isolamento & purificação , Estudos Retrospectivos , Prevalência , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Ativação Viral/efeitos dos fármacos , Tailândia/epidemiologia , Carga Viral
6.
Virology ; 595: 110096, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38710129

RESUMO

Herpes stromal keratitis is the leading cause of infectious blindness in the western world. Infection by HSV1 is most common, but VZV and hCMV also infect the cornea. Multiple models of HSV1 corneal infection exist, but none for VZV and hCMV because of their host specificity. Here, we used commercially available 3D human corneal epithelial equivalents (HCEE) to study infection by these herpesviruses. HCEE was infected by HSV-1 and hCMV without requiring scarification and resulted in spreading infections. Spread of HSV-1 infection was rapid, while that of hCMV was slow. In contrast, infections with VZV required damage to the HCEE and did not spread. Acyclovir dramatically reduced replication of HSV-1 in this model. We conclude that highly quality-controlled, readily available HCEE is a useful model to study human-restricted herpesvirus infection of the human corneal epithelium and for screening of antiviral drugs for treating HSK in an 3D model system.


Assuntos
Antivirais , Epitélio Corneano , Herpesvirus Humano 1 , Ceratite Herpética , Humanos , Ceratite Herpética/virologia , Ceratite Herpética/tratamento farmacológico , Epitélio Corneano/virologia , Epitélio Corneano/patologia , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 1/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/uso terapêutico , Herpesvirus Humano 3/fisiologia , Herpesvirus Humano 3/efeitos dos fármacos , Citomegalovirus/fisiologia , Citomegalovirus/efeitos dos fármacos , Replicação Viral , Aciclovir/farmacologia , Aciclovir/uso terapêutico , Células Epiteliais/virologia , Modelos Biológicos
7.
Ugeskr Laeger ; 186(15)2024 Apr 08.
Artigo em Dinamarquês | MEDLINE | ID: mdl-38708697

RESUMO

Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for therapy-refractory CMV infection or when other treatment options cannot be used. The patient in this case report was a CMV-infected liver transplant recipient, who developed a severe erythema and high CMV DNA during valganciclovir therapy. Toxic epidermal necrolysis was suspected. The patient was treated with maribavir, and both CMV DNA and the skin normalised. This case illustrates that maribavir is a useful alternative to other antiviral drugs for CMV infection.


Assuntos
Antivirais , Infecções por Citomegalovirus , Diclororribofuranosilbenzimidazol/análogos & derivados , Transplante de Fígado , Ribonucleosídeos , Humanos , Infecções por Citomegalovirus/tratamento farmacológico , Transplante de Fígado/efeitos adversos , Antivirais/uso terapêutico , Ribonucleosídeos/uso terapêutico , Ribonucleosídeos/administração & dosagem , Benzimidazóis/uso terapêutico , Benzimidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Citomegalovirus/isolamento & purificação , Citomegalovirus/efeitos dos fármacos
8.
Sci Rep ; 14(1): 10253, 2024 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-38704431

RESUMO

The tegument protein pp150 of Human Cytomegalovirus (HCMV) is known to be essential for the final stages of virus maturation and mediates its functions by interacting with capsid proteins. Our laboratory has previously identified the critical regions in pp150 important for pp150-capsid interactions and designed peptides similar in sequence to these regions, with a goal to competitively inhibit capsid maturation. Treatment with a specific peptide (PepCR2 or P10) targeted to pp150 conserved region 2 led to a significant reduction in murine CMV (MCMV) growth in cell culture, paving the way for in vivo testing in a mouse model of CMV infection. However, the general pharmacokinetic parameters of peptides, including rapid degradation and limited tissue and cell membrane permeability, pose a challenge to their successful use in vivo. Therefore, we designed a biopolymer-stabilized elastin-like polypeptide (ELP) fusion construct (ELP-P10) to enhance the bioavailability of P10. Antiviral efficacy and cytotoxic effects of ELP-P10 were studied in cell culture, and pharmacokinetics, biodistribution, and antiviral efficacy were studied in a mouse model of CMV infection. ELP-P10 maintained significant antiviral activity in cell culture, and this conjugation significantly enhanced P10 bioavailability in mouse tissues. The fluorescently labeled ELP-P10 accumulated to higher levels in mouse liver and kidneys as compared to the unconjugated P10. Moreover, viral titers from vital organs of MCMV-infected mice indicated a significant reduction of virus load upon ELP-P10 treatment. Therefore, ELP-P10 has the potential to be developed into an effective antiviral against CMV infection.


Assuntos
Antivirais , Infecções por Citomegalovirus , Elastina , Muromegalovirus , Peptídeos , Fosfoproteínas , Proteínas da Matriz Viral , Animais , Elastina/química , Elastina/metabolismo , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Camundongos , Antivirais/farmacologia , Antivirais/farmacocinética , Antivirais/química , Peptídeos/farmacologia , Peptídeos/química , Muromegalovirus/efeitos dos fármacos , Humanos , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/química , Citomegalovirus/efeitos dos fármacos , Capsídeo/metabolismo , Capsídeo/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/farmacocinética , Modelos Animais de Doenças , Polipeptídeos Semelhantes à Elastina
9.
Br J Haematol ; 204(6): 2378-2389, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38581290

RESUMO

To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).


Assuntos
Antivirais , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Citomegalovirus , Citomegalovirus , Quinazolinas , Ativação Viral , Humanos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Masculino , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/etiologia , Feminino , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Adulto , Estudos Retrospectivos , Adolescente , Pessoa de Meia-Idade , Criança , Ativação Viral/efeitos dos fármacos , Antivirais/uso terapêutico , Quinazolinas/uso terapêutico , Quinazolinas/farmacologia , Pré-Escolar , Farmacorresistência Viral , Adulto Jovem , Lactente , Idoso , Acetatos
11.
BMC Infect Dis ; 24(1): 443, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38671346

RESUMO

BACKGROUND: Cytomegalovirus (CMV) colitis significantly complicates the course of inflammatory bowel disease (IBD), frequently leading to severe flare-ups and poor outcomes. The role of antiviral therapy in hospitalized IBD patients with CMV colitis is currently under debate. This retrospective analysis seeks to clarify the influence of antiviral treatment on these patients. METHODS: We retrospectively reviewed IBD patients diagnosed with CMV colitis via immunohistochemistry staining from colonic biopsies at a major tertiary center from January 2000 to May 2021. The study focused on patient demographics, clinical features, risk factors, prognostic indicators, and antiviral treatment outcomes. RESULTS: Among 118 inpatients, 42 had CMV colitis. Risk factors included hypoalbuminemia and antibiotic use. IBD patients with CMV colitis receiving < 14 days of antiviral therapy had higher complication (72% vs. 43%, p = 0.028) and surgery rates (56% vs. 26%, p = 0.017) compared to those without CMV. Adequate antiviral therapy (≥ 14 days) significantly reduced complications in the CMV group (29% vs. 72%, p = 0.006), especially in Crohn's disease (20% vs. 100%, p = 0.015). Independent predictors of IBD-related complications were CMV colitis (Odds Ratio [OR] 3.532, 90% Confidence Interval [CI] 1.012-12.331, p = 0.048), biological treatment failure (OR 4.953, 95% CI 1.91-12.842, p = 0.001), and adequate antiviral therapy (OR 0.108, 95% CI 0.023-0.512, p = 0.005). CONCLUSION: CMV colitis and a history of biological treatment failure increase complication risks in IBD patients. Adequate antiviral therapy significantly mitigates these risks, highlighting its importance in managing IBD patients with CMV colitis.


Assuntos
Antivirais , Colite , Infecções por Citomegalovirus , Doenças Inflamatórias Intestinais , Humanos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/virologia , Masculino , Feminino , Antivirais/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/complicações , Adulto , Colite/virologia , Colite/tratamento farmacológico , Colite/complicações , Citomegalovirus/efeitos dos fármacos , Fatores de Risco , Idoso , Pacientes Internados , Resultado do Tratamento
12.
J Med Virol ; 96(4): e29609, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38647051

RESUMO

This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.


Assuntos
Antivirais , Benzimidazóis , Análise Custo-Benefício , Infecções por Citomegalovirus , Diclororribofuranosilbenzimidazol/análogos & derivados , Anos de Vida Ajustados por Qualidade de Vida , Ribonucleosídeos , Humanos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/economia , Antivirais/uso terapêutico , Antivirais/economia , Ribonucleosídeos/uso terapêutico , Ribonucleosídeos/economia , Benzimidazóis/uso terapêutico , Benzimidazóis/economia , Estados Unidos , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , Farmacorresistência Viral , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Genótipo , Transplantados
13.
J Clin Virol ; 172: 105678, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38688164

RESUMO

BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown. METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia. RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different. CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG. TRIAL REGISTRATION NUMBER: NCT01329185.


Assuntos
Antivirais , Infecções por Citomegalovirus , Ganciclovir , Transplante de Rim , Transplantados , Valaciclovir , Valganciclovir , Humanos , Valaciclovir/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Valganciclovir/uso terapêutico , Valganciclovir/administração & dosagem , Transplante de Rim/efeitos adversos , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Masculino , Feminino , Adulto , Criança , Pessoa de Meia-Idade , Adolescente , Ganciclovir/análogos & derivados , Ganciclovir/uso terapêutico , Ganciclovir/administração & dosagem , Ganciclovir/efeitos adversos , Viremia/prevenção & controle , Carga Viral , Adulto Jovem , Valina/análogos & derivados , Valina/uso terapêutico , Valina/administração & dosagem , Citomegalovirus/imunologia , Citomegalovirus/efeitos dos fármacos , Pré-Escolar , Aciclovir/uso terapêutico , Aciclovir/análogos & derivados , Aciclovir/administração & dosagem , Aciclovir/efeitos adversos , Idoso , Resultado do Tratamento , Incidência
14.
Eur J Med Chem ; 271: 116412, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38643669

RESUMO

New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared through a convergent synthesis by olefin cross-metathesis as the key step. Several acyclic nucleoside 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug exhibited in vitro antiviral activity in submicromolar or nanomolar range against varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpes virus type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus (VV), with good selective index (SI). Among them, the analogue 9c (LAVR-289) proved markedly inhibitory against VZV wild-type (TK+) (EC50 0.0035 µM, SI 740) and for thymidine kinase VZV deficient strains (EC50 0.018 µM, SI 145), with a low morphological toxicity in cell culture at 100 µM and acceptable cytostatic activity resulting in excellent selectivity. Compound 9c exhibited antiviral activity against HCMV (EC50 0.021 µM) and VV (EC50 0.050 µM), as well as against HSV-1 (TK-) (EC50 0.0085 µM). Finally, LAVR-289 (9c) deserves further (pre)clinical investigations as a potent candidate broad-spectrum anti-herpesvirus drug.


Assuntos
Antivirais , Vírus de DNA , Testes de Sensibilidade Microbiana , Pró-Fármacos , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Pró-Fármacos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/química , Humanos , Vírus de DNA/efeitos dos fármacos , Relação Estrutura-Atividade , Herpesvirus Humano 1/efeitos dos fármacos , Estrutura Molecular , Herpesvirus Humano 3/efeitos dos fármacos , Organofosfonatos/farmacologia , Organofosfonatos/química , Organofosfonatos/síntese química , Citomegalovirus/efeitos dos fármacos , Relação Dose-Resposta a Droga , Vaccinia virus/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos
15.
Leuk Lymphoma ; 65(6): 816-824, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38475670

RESUMO

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.


Assuntos
Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Foscarnet , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Valganciclovir , Viremia , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Citomegalovirus/etiologia , Valganciclovir/uso terapêutico , Masculino , Feminino , Viremia/tratamento farmacológico , Adulto , Antivirais/uso terapêutico , Foscarnet/uso terapêutico , Pessoa de Meia-Idade , Citomegalovirus/efeitos dos fármacos , Estudos Retrospectivos , Adulto Jovem , Idoso , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Resultado do Tratamento , Leucemia/terapia , Leucemia/complicações , Leucemia/mortalidade
16.
Transplant Cell Ther ; 30(5): 538.e1-538.e10, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38331195

RESUMO

Cytomegalovirus (CMV) reactivations cause significant morbidity in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy) is associated with an increased risk of CMV infections. Data are limited comparing HSCT with PTCy performed from matched sibling donors (MSDs), matched unrelated donors (MUDs), and haploidentical (Haplo) donors. In the present study, we aimed to characterize CMV reactivation and recurrence in patients with hematologic malignancies undergoing HSCT from MSD, MUD, and Haplo donors using PTCy as GVHD prophylaxis in the pre-letermovir era. We also analyzed risk factors of CMV reactivation, including GVHD as a time-dependent variable, on the incidence and mortality associated with CMV infections. We analyzed CMV reactivation in patients undergoing HSCT from 160 MSDs, 124 MUDs, and 82 Haplo donors from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus, and mycophenolate mofetil was given irrespective of donor type. Overall, 46% of patients had at least 1 CMV reactivation. The 1-year cumulative incidence of CMV infection was 39% for MSD, 44% for MUD, and 62% for Haplo donors (P < .001), with 96% of reactivations occurring before day +100. Multivariate analysis identified factors associated with the first CMV reactivation, including Haplo donor, positive recipient CMV serology, older patient age, and grade II-IV acute GVHD. The 1-year cumulative incidence of second reactivation from HSCT was 13%. Recipient CMV seropositivity, older patient age, and grade II-IV acute GVHD, but not type of donor, were identified as adverse factors for second CMV reactivation in multivariate analysis. The 1-year cumulative incidence of a third reactivation post HSCT was 4.4%. Ten cases of CMV disease were recorded, with no attributable deaths. Nevertheless, the risk for nonrelapse mortality was greater for patients who experienced CMV reactivation in multivariate time-dependent Cox model analysis. CMV reactivation is frequent in HSCT with PTCy in patients not receiving letermovir prophylaxis. Identified risk factors include the use of a Haplo donor, recipient CMV seropositivity, and grade II-IV acute GVHD. The prevalence of recurrent CMV reactivations is a noteworthy issue, especially after acute GVHD, warranting trials of secondary prophylaxis strategies.


Assuntos
Ciclofosfamida , Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Ativação Viral , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Ativação Viral/efeitos dos fármacos , Ciclofosfamida/uso terapêutico , Ciclofosfamida/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/epidemiologia , Transplante Homólogo/efeitos adversos , Citomegalovirus/imunologia , Citomegalovirus/efeitos dos fármacos , Idoso , Adulto Jovem , Doadores de Tecidos , Adolescente , Transplante Haploidêntico/efeitos adversos , Fatores de Risco , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Neoplasias Hematológicas/terapia , Doadores não Relacionados , Antígenos HLA/imunologia , Irmãos
17.
Int J Antimicrob Agents ; 63(5): 107116, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38401774

RESUMO

Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT). Immunosuppressors are used universally to prevent graft-vs-host disease in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infection, but there is also evidence of their specific interference with viral infection. This study evaluated the antiviral activity of immunosuppressors commonly used in clinical practice in SOT and HSCT recipients in vitro to determine whether their use could be associated with reduced risk of HAdV and HCMV infection. Cyclophosphamide, tacrolimus, cyclosporine, mycophenolic acid, methotrexate, everolimus and sirolimus presented antiviral activity, with 50% inhibitory concentration (IC50) values at low micromolar and sub-micromolar concentrations. Mycophenolic acid and methotrexate showed the greatest antiviral effects against HAdV (IC50=0.05 µM and 0.3 µM, respectively) and HCMV (IC50=10.8 µM and 0.02 µM, respectively). The combination of tacrolimus and mycophenolic acid showed strong synergistic antiviral activity against both viruses, with combinatory indexes (CI50) of 0.02 and 0.25, respectively. Additionally, mycophenolic acid plus cyclosporine, and mycophenolic acid plus everolimus/sirolimus showed synergistic antiviral activity against HAdV (CI50=0.05 and 0.09, respectively), while methotrexate plus cyclosporine showed synergistic antiviral activity against HCMV (CI50=0.29). These results, showing antiviral activity in vitro against both HAdV and HCMV, at concentrations below the human Cmax values, may be relevant for the selection of specific immunosuppressant therapies in patients at risk of HAdV and HCMV infections.


Assuntos
Adenovírus Humanos , Antivirais , Citomegalovirus , Imunossupressores , Humanos , Imunossupressores/farmacologia , Antivirais/farmacologia , Adenovírus Humanos/efeitos dos fármacos , Citomegalovirus/efeitos dos fármacos , Sinergismo Farmacológico , Concentração Inibidora 50 , Ácido Micofenólico/farmacologia , Tacrolimo/farmacologia , Ciclosporina/farmacologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/prevenção & controle
19.
Transpl Infect Dis ; 26(3): e14229, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38214192

RESUMO

The Comparison of Antiviral Preventative Strategies In Liver Transplant (CAPSIL) study showed pre-emptive therapy (PET) to be superior to antiviral prophylaxis for Cytomegalovirus (CMV) disease prevention in high-risk CMV seronegative liver transplant recipients (LTRs) with seropositive donors (D+R-). Despite the statistical superiority of PET over prophylaxis in research settings, PET is perceived as a logistically more complex strategy that requires careful coordination of weekly CMV PCR testing, prompt initiation of CMV antivirals upon viremia detection, and timely cessation of antivirals following viremia resolution. Transplant centers may be hesitant to use PET for CMV disease prevention in D+R- LTRs out of concern that PET coordination is not feasible in clinical practice. We recently described our experience using PET in CMV D+R- LTRs in a real-world setting, and found it to be as effective for CMV disease prevention as PET performed as part of a clinical trial. Here, we describe a systematic approach for PET implementation in real-world settings and provide practical tools to address anticipated challenges. This framework can support transplant programs in overcoming logistical barriers to PET and incorporating an evidence-based and cost-effective CMV prevention strategy into routine care for high-risk CMV D+R- LTRs.


Assuntos
Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Transplante de Fígado , Doadores de Tecidos , Humanos , Infecções por Citomegalovirus/prevenção & controle , Transplante de Fígado/efeitos adversos , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/isolamento & purificação , Transplantados , Viremia/prevenção & controle
20.
J Virol ; 97(10): e0069623, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37796129

RESUMO

IMPORTANCE: Human cytomegalovirus (HCMV) infection is the leading cause of non-heritable birth defects worldwide. HCMV readily infects the early progenitor cell population of the developing brain, and we have found that infection leads to significantly downregulated expression of key neurodevelopmental transcripts. Currently, there are no approved therapies to prevent or mitigate the effects of congenital HCMV infection. Therefore, we used human-induced pluripotent stem cell-derived organoids and neural progenitor cells to elucidate the glycoproteins and receptors used in the viral entry process and whether antibody neutralization was sufficient to block viral entry and prevent disruption of neurodevelopmental gene expression. We found that blocking viral entry alone was insufficient to maintain the expression of key neurodevelopmental genes, but neutralization combined with neurotrophic factor treatment provided robust protection. Together, these studies offer novel insight into mechanisms of HCMV infection in neural tissues, which may aid future therapeutic development.


Assuntos
Anticorpos Neutralizantes , Infecções por Citomegalovirus , Citomegalovirus , Expressão Gênica , Fatores de Crescimento Neural , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Células-Tronco Pluripotentes Induzidas/citologia , Fatores de Crescimento Neural/farmacologia , Fatores de Crescimento Neural/uso terapêutico , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Organoides/citologia , Organoides/metabolismo , Organoides/virologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , Proteínas do Envelope Viral/antagonistas & inibidores , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus/efeitos dos fármacos
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