Oral Valganciclovir Is Noninferior to Intravenous Ganciclovir for the Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients

Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily valganciclovir for 28 days. A total of 321 patients were evaluated (valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for valganciclovir and 48.4% for ganciclovir (95% CI -14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study.     

Nephrotic syndrome in a mother and her infant: relationship with cytomegalovirus infection

This case report describes infantile nephrotic syndrome (NS) in a baby girl with a clinically severe cytomegalovirus (CMV) infection. Culture of the baby's urine was positive for CMV and IgM anti-CMV antibodies were detected. After an unsuccessful course of corticosteroids, gancyclovir treatment was started and a remission of cutaneous, pulmonary, and renal symptoms was achieved. As the mother also developed NS at the end of pregnancy, a common etiology could be postulated, although there were no signs of recent CMV infection in the mother, only anti-CMV IgG. The relationship between CMV infection and glomerular disease is still unclear: NS may represent another manifestation of CMV disease.     

巨细胞病毒肝炎患儿血清细胞因子水平测定及其临床意义

目的　研究巨细胞病毒 (CMV)肝炎患儿血清干扰素 α(IFN α)、白细胞介素 8(IL 8)和肿瘤坏死因子 α(TNF α)水平的变化及其临床意义。方法　应用ELISA法检测 35例CMV肝炎患儿血清中上述三种细胞因子的含量 ,并对其两两之间进行了相关性分析。结果　CMV肝炎组患儿IFN α、IL 8、TNF α的含量分别为 (770 .3± 2 0 5 .4 )ng/L、(41.9± 2 2 .5 )ng/L和 (10 33.2± 388.5 )ng/L ,非常显著高于正常对照组 (P <0 .0 1)。相关性研究发现IFN α与TNF α呈显著正相关 (r =0 .35 6 ,P <0 .0 5 )。结论　血清细胞因子明显增高与CMV肝炎的病理变化和病损程度有着密切的联系     

Assay of cytomegalovirus susceptibility to ganciclovir in renal and heart transplant recipients

Ganciclovir (GCV) prophylaxis or pre-emptive therapy significantly reduce the rate of cytomegalovirus (CMV) disease and viremia, but increase the potential for emergence of ganciclovir-resistant CMV strains. The inhibitor concentration at 50% (IC(50)) of GCV from 156 CMV isolates from 59 renal or heart transplant recipients was calculated by means of a rapid phenotypic susceptibility assay. Twenty-seven strains were from 14 patients undergoing GCV therapy. The IC(50) was higher in patients under the prophylaxis regimen. One CMV strain, from a heart transplant recipient, became GCV-resistant after 1 month of therapy (IC(50)=13.7 micromol/l). These data, together with clinical and virological markers, suggested that a switch to foscarnet was necessary, and good evolution was observed. Thus, assay of CMV susceptibility to GCV could be helpful in clinical management.     

实质器官移植术后血浆IL-18、IL-10、IL-4检测在人巨细胞病毒感染中的意义

目的 探讨实质器官移植术后血浆中白介素18（IL－18）、白介素10（IL－10）、白介素4（IL－4）水平的检测在人巨细胞病毒（HCMV）感染中的意义。方法 对24例实质器官移植受者，用免疫组化法监测HCMV抗原血症。然后采用ELISA法测定血浆中IL－18、IL－10及IL－4的水平。结果 HCMV抗原阳性组IL－18的水平高于阴性组（P＜0.01），IL－10及IL－4的水平低于阴性组（均P＜0.05）。结论 血浆IL－18的水平可作为预测移植患者HCMV感染的一个有效指标，IL－10及IL－4的水平则可作为患者HCMV感染后体内免疫抑制程度的监测指标之一。     

Interactions Between Cytomegalovirus, Human Herpesvirus-6, and the Recurrence of Hepatitis C After Liver Transplantation

Recurrence of hepatitis C (HCV) following liver transplantation is common. Herpesvirus reactivation following transplant may have an immunomodulatory effect resulting in increased HCV replication. We studied whether cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6) may be associated with HCV recurrence and viral load after transplant. We prospectively followed 66 HCV liver-transplant recipients with serial viral load testing for CMV and HHV-6. Infection and viral load were correlated with the development of biopsy-proven HCV recurrence and HCV viral loads. Histologic recurrence of HCV occurred in 41/66 (62.1%) patients. In the primary analysis, CMV infection and disease, and HHV-6 infection were not associated with HCV recurrence. Peak CMV and HHV-6 viral loads were not significantly different in patients with and without recurrence. No correlation was observed between HCV viral loads at 1 and 3 months post-transplant and peak HHV-6 or CMV viral loads. In a subgroup analysis, HHV-6 infection was associated with the development of more severe recurrence (hepatitis and/or fibrosis score > or = 2) (p = 0.01). Also, fibrosis scores at last follow up were higher in patients with CMV disease (1.67 vs. 0.56; p = 0.016) and in patients with HHV-6 infection (1.18 vs. 0.55; p = 0.031). In conclusion, HHV-6 and CMV infection and viral load were not associated with increased overall rates of HCV recurrence or HCV viral load after liver transplantation but may be associated with more severe forms of recurrence.     

Correlation between the intensity of cytomegalovirus infection and the amount of perivasculitis in aortic allografts

Abstract  We previously demonstrated that cytomegalovirus (CMV) infection enhanced perivascular inflammation in rat aortic allografts. In this study, we investigated the relationship between the CMV infection load and the magnitude of perivasculitis (chronic rejection) in aortic transplants. Rats received or-thotopic abdominal aortic grafts, different degrees of total body irradiation (TBI) for immunosuppres-sion and CMV inoculation. The spleens of the rats receiving 5 Gy of TBI contained more infectious virus and viral antigens than those of rats receiving 3 Gy of TBI or no TBI. Although the number of inflammatory cells infiltrating the perivascular area was decreased after TBI, CMV infection resulted in increased perivasculitis in rats that received 5 Gy of TBI as compared to non-infected animals. This virus-induced effect was characterized predominantly by an increased T-cell infiltration, including CD4 and CD8 T-cells. It is concluded that an enhanced systemic CMV infection during severe immunosuppressive therapy can accelerate the development of chronic rejection, which seems to be mediated mainly by T-cells.     

Cytomegalovirus Disease in High-Risk Transplant Recipients Despite Ganciclovir or Valganciclovir Prophylaxis

The clinical patterns and predictors of cytomegalovirus (CMV) disease in kidney and/or pancreas transplant patients on ganciclovir (1.0 g po t.i.d.) or valganciclovir (450 mg po q.d.) prophylaxis were studied. This is a retrospective analysis of 129 transplant recipients. Median follow up was 12 months (range, 6-18 months). The overall incidence of CMV disease at 1-year post-transplant was 14% (4% tissue-invasive, 10% noninvasive). Seventeen of 18 patients were diagnosed with CMV after completion of 3 months' prophylaxis (median 8 weeks, range, 2-28 weeks). Induction treatment with thymoglobulin, and Donor +/Recipient - CMV status were the strongest predictors for the development of CMV disease. Cytomegalovirus incidence was not different between patients treated with ganciclovir or valganciclovir (15 vs. 17%, respectively). Valganciclovir (450 mg q.d.) is as effective as oral ganciclovir in CMV prophylaxis. High-risk individuals might require higher doses or longer duration of valganciclovir treatment.     

Differences in CMV-Specific T-Cell Levels and Long-Term Susceptibility to CMV Infection after Kidney, Heart and Lung Transplantation

Patients after kidney, heart and lung transplantation differ in their immunosuppressive drug regimens and in susceptibility to infectious complications with cytomegalovirus (CMV). In this study, CMV-specific T-cell responses were characterized in long-term transplant recipients and associated with the frequency of infectious complications. CMV-reactive CD4 T cells from 50 healthy controls, 68 renal, 14 heart and 24 lung transplant recipients were flow cytometrically quantified by the induction of cytokines after specific stimulation. Moreover, the immunosuppressive effect of calcineurin inhibitors on specific T-cell reactivity was quantified in vitro and compared with responses in vivo. Median CMV-specific T-cell frequencies in long-term renal (1.48%; range 0.06-17.26%) and heart transplant recipients (0.90%; 0.13-12.49%) did not differ from controls (1.82%; 0.26-21.00%). In contrast, CMV-specific T-cell levels were significantly lower in lung transplant recipients (0.50%; <0.05-4.98%) and showed a significant correlation with the frequency of infectious episodes (r =-0.57, p = 0.005). The differences within the groups were associated with increasing dosages of immunosuppressive drugs, as exemplified for calcineurin inhibitors that dose dependently reduced specific T-cell reactivity in vitro. In conclusion, monitoring CMV-specific CD4 T cells may serve as a measure for long-term disease susceptibility and may contribute to an improved management of CMV complications after lung transplantation.     

Valganciclovir Dosing According to Body Surface Area and Renal Function in Pediatric Solid Organ Transplant Recipients

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients ≤2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 × body surface area × creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 ± 11.9 μg * h/mL; liver 61.7 ± 29.5 μg * h/mL; heart 58.0 ± 21.8 μg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults