Preemptive Treatment Of Cytomegalovirus Infection Research Articles

Does the cytomegalovirus infection cause kidney transplant rejection in Erbil city patients, Kurdistan region of Iraq?

Does the cytomegalovirus infection cause kidney transplant rejection in Erbil city patients, Kurdistan region of Iraq?

Maribavir for Preemptive Treatment of Cytomegalovirus Reactivation

BackgroundMaribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known.MethodsIn a phase 2, open-label, maribavir dose–blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment.ResultsOf the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available — 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir.ConclusionsMaribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events — notably dysgeusia — and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.)

Half-dose ganciclovir preemptive treatment of cytomegalovirus infection after pediatric allogeneic hematopoietic stem cell transplantation.

Ganciclovir (GCV) has been widely used as preemptive therapy after hematopoietic stem cell transplantation (HSCT), although bone marrow suppression is a known accompaniment, with secondary infection or bleeding as potential complications. Our aim was to evaluate clinical outcomes in pediatric patients with low cytomegalovirus (CMV) antigenemia levels using half the dosage of GCV generally given preemptively. Patients received half doses of intravenous GCV (5 mg/kg once daily, 6 days/week) at CMV antigenemia levels <10/200,000 cells. At higher levels of CMV antigenemia, conventional doses of GCV (5 mg/kg every 12 h) were administered. A total of 130 patients were evaluated, detecting CMV antigenemia in 87 (66.9%). Of these patients, 74 (85.1%) were treated preemptively with half-dose GCV, which proved effective as sole therapy in 51 (68.9%). CMV retinitis developed in 4 patients, 2 of whom initially were given half-dose GCV. All infections resolved successfully, with no CMV-related deaths. CMV seropositivity in recipients was the only significant risk factor for positive CMV antigenemia (hazard ratio [HR] = 10.05, P = 0.046). Compared with half-dose GCV administration, conventional GCV dosing resulted in a higher rate of severe neutropenia, defined as absolute neutrophil count <0.5 × 10(9) /L (HR = 4.30, P = 0.015). Half-dose GCV therapy at CMV antigenemia levels <10/200,000 cells is an effective and safe means of preemptively treating pediatric CMV infection after HSCT.

Risk factors analysis of cytomegalovirus infection after nonmyeloablative allogeneic peripheral blood stem cell transplantation

The aim of this study was to analyze the risk factors of cytomegalovirus (CMV) infection and CMV disease after nonmyeloablative allogeneic hematopoietic stem cell transplantation(NST) and develop a rational strategy for the diagnosis, monitoring and preemptive treatment of CMV infection. The Clinical data of 80 patients undergoing NST from November 2009 to November 2012 in the hospital 307 were retrospectively analyzed. The cytomegalovirus load in peripheral blood of patients was detected by using RT-PCR. The results indicated that the incidence of CMV infection was 77.5% (62/80), and the median time for the positive CMV-DNA firstly detected by RT-PCR was day 35 (17-133) after NST. The total of 100-day cumulative incidence of CMV disease was 11.3%(9/80) after early preemptive therapy. Both univariate and multivariate analysis showed thymoglobulin (ATG) used in preconditioning regimen, other herpesvirus infection and fungal infection in medical history before NST were the risk factors of CMV infection after NST.Univariate analysis revealed that CMV viremia and ATG used in preconditioning regimen were the risk factors for CMV disease, while the same result was not found in the multivariate analysis.The incidence of CMV infection in patients with II-IV grade of aGVHD was 91.3%,while the incidence of CMV infection in patients with 0-1 grade of aGVHD was 71.9% (P = 0.06), it seems that II-IV grade of aGVHD was not the risk factor of CMV infection for NST. It is concluded that the ATG used in preconditioning regimen may increase the incidence of both CMV infection and CMV disease after NST. CMV infection easily accompanies by other herpesvirus infection and fungal infection.Therefore other herpesvirus infection and fungal infection should be attentively monitored and prevented after trans-plantation.

Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti-HCMV drug in development, acting via a novel mechanism of action. In this proof-of-concept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14-day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open-label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV-DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti-CMV drug.

Cytomegalovirus in hematological malignancies

Cytomegalovirus (CMV) infection frequently causes cytopenia in hematopoietic stem cell transplant setting where there are clear cut recommendations for prophylaxis, screening and pre-emptive treatment of CMV infection [1]. However, evidence of CMV infection in hematological malignancies other than stem cell transplant setting is lacking. A retrospective, single centre study of autopsied patients of acute leukemia, chronic leukemia or myelodysplastic syndrome (without stem cell transplant), reported a low, but rising prevalence of CMV pneumonitis over a 5-year period, with a case fatality rate of 57% [2]. Kanvinde, et al. [3] describe 13 episodes of CMV in 11 cases of hematological malignancy, which were treated with intravenous gancyclovir. These cases were diagnosed based on detection of antigen or DNA, of which, nearly half were diagnosed by a qualitative PCR which is not the standard method for diagnosing CMV infection. Further, none of these cases had demonstration of virus by culture or histopathology. Few of these episodes were associated with other documented viral or bacterial infections which by themselves are known to cause prolonged cytopenias. Further, two of these patients had resolution of their symptoms even before initiation of gancyclovir. It would be reasonable to state that these patients may have had evidence of CMV infection but certainly CMV disease was not demonstrated in any case, and thus none of these patients can be attributed to have CMV-related cytopenia.

Prognostic Impact of Recipient and Donor CMV Serostatus in Acute Leukemia Patients After Allogeneic Stem Cell Transplantation At the Era of Preemptive Therapy.

AbstractAbstract 3110 Background:Monitoring and (preemptive) treatment of cytomegalovirus (CMV) infection or disease have been implemented in clinical routine algorithms in patients after allogeneic stem transplantation (allo-SCT) in the early nineties and resulted in a dramatic decrease of CMV disease from 20–30% to less than 5% in recent years. However, a significantly reduced relapse incidence (RI) in acute myeloid leukemia (AML) patients with vs. without early CMV replication has been reported just recently. Larger analyses evaluating the prognostic impact of recipient and donor CMV serostatus - as one of the most important risk factors for CMV infection and disease - are lacking at the era of preemptive treatment of CMV infection. Design and methods:We analyzed the prognostic impact of the (pretransplant) recipient and donor CMV serostatus in 16 628 adult de novo acute leukemia patients who underwent allo-SCT between 1998 and 2009 and are documented in the European Bone Marrow Transplantation (EBMT) database (Cohort I). Additionally, 544 patients with secondary AML (e.g. following myeloproliferative neoplasms) who underwent allo-SCT and were reported to the German Registry for Stem Cell Transplantation (DRST) were analyzed according to the prognostic impact of the CMV serostatus (Cohort II). Finally, 97 acute leukemia patients allografted at the Charité University Hospital (Berlin, Germany) were studied more in detail including other parameters such as kinetics of CMV infection and hematopoietic recipient/donor chimerism (Cohort III). Results:Recipient and/or donor CMV seropositivity was associated with a reduced 2-year leukemia-free survival (LFS) (44% vs. 49%, p<0.001) and overall survival (OS) (50% vs. 56%, p<0.001) in de novo acute leukemia patients (Cohort I). These observations were mainly due to an increased non-relapse mortality (NRM) (23% vs. 20%, p<0.001) and strongest in recipients allografted from a non-HLA identical sibling. However, also higher RI was noted especially for acute lymphoblastic leukemia (ALL), resulting in a markedly decreased 2-year OS (46% vs. 55%, p<0.001) in these patients. The negative prognostic impact of recipient and/or donor CMV seropositivity with respect to LFS, OS, NRM and RI remained in a multivariate Cox regression model including different other parameters (e.g. conditioning type). Conversely, the donor CMV serostatus had no significant prognostic impact among CMV seropositive recipients. Recipient CMV seropositivity was further associated with a significantly increased frequency of death due to interstitial pneumonitis, but decreased incidence of both chronic and II-IV° acute graft-versus-host disease (28% vs. 31%, p<0.001). However, it had no significant impact on the incidence of graft failure. Also in secondary AML (Cohort II) recipient and donor CMV seronegativity was associated with a superior 2-year LFS (48% vs. 41%) and OS (54% vs. 44%), but decreased RI (27% vs. 30%) and NRM (25% vs. 31%). The negative impact of CMV seropositivity of the recipient and/or the donor with respect to OS likewise remained in this cohort of secondary AML in a multivariate Cox regression model (Hazard ratio 1.4, p=0.03). Finally, analysis of cohort III showed that CMV seropositive vs. CMV seronegative patients had a significantly reduced OS even in the absence of CMV antigenemia and less frequently had a complete day +30 hematopoietic chimerism (68% vs. 92%, p=0.02). Conclusion:The recipient and donor CMV serostatus still has an important prognostic effect in acute leukemia patients after allo-SCT - particularly in ALL and those allografted from a non-HLA identical sibling - despite the implementation of most sophisticated techniques for monitoring and (preemptive) treatment of CMV in recent years. The increased RI in cases with CMV seropositivity of the recipient and/or the donor argues against a clinically important ‘virus-versus-leukemia effect′ which has been suggested just recently. Disclosures:No relevant conflicts of interest to declare.

Characteristics and influencing factors of CD19+ B cell reconstitution in patients following haploidentical/mismatched hematopoietic stem cell transplantation

In patients undergoing hematopoietic stem cell transplantation (HSCT), B cells exert important, prolonged effects that provide protection from infection. In this study, we analyzed characteristics and influencing factors of CD19+ B cell reconstitution in 83 patients who underwent unmanipulated haploidentical/mismatched blood and bone marrow transplantation. Of these patients, 45% showed a normal CD19+ B cell count at +360 days. Factors associated with lower CD19+ B cell levels were as follows: aGVHD grades II-IV had a trend to affect CD19+ B cell reconstitution at +180days; clinically extensive cGVHD was significantly associated with CD19+ B cell deficiency at +360days and serum IgG level at +180 and +360days; cytomegalovirus (CMV) infection occurred after +38days was correlated with lower B cell level at both +90 and +360days, while those occurred before +38days did not show this effect; glucocorticoids used around +90 and +180days was associated with lower CD19+ B cell levels at +90 and +360days, respectively, especially in patients that did not experience extensive cGVHD. In contrast, the number of HLA-mismatched locus positively correlated with CD19+ B cell at +90days and serum IgG level at +180days. In conclusion, CD19+ B cell recovery after haploidentical/mismatched HSCT was mainly influenced by GVHD and/or its treatment, CMV infection that occurred later (after +38days) and use of glucocorticoids. Improvement of B cell recovery is likely to be achieved through effective prophylaxis of GVHD, minimized use of glucocorticoids, and preemptive treatment of CMV infection occurring after +38days. More HLA-mismatched loci may initiate a stronger humoral response toward alloantigens >180days after HSCT, which may be beneficial for the eradication of minimal residual disease and protection from infection.

Oral valganciclovir &lt;i&gt;versus&lt;/i&gt; intravenous ganciclovir as preemptive treatment for cytomegalovirus infection after living donor liver transplantation: A randomized trial

It is unclear whether valganciclovir (VGCV) is effective compared with intravenous ganciclovir (GCV) for preemptive therapy of cytomegalovirus (CMV) infection in living donor liver transplantation (LDLT). A randomized trial was conducted to compare the efficacy of oral VGCV with intravenous GCV for preemptive treatment of CMV infection after LDLT. Patients who developed CMV infection within 6 months after LDLT at Tokyo University Hospital were randomly assigned to the VGCV or GCV group and received either oral VGCV 900 mg/day or intravenous GCV 5 mg/kg twice daily, respectively. The primary endpoint was the treatment success rate. Secondary endpoints were recurrence of CMV infection within 1 year after finishing the treatment, and safety and tolerability of the treatment. Twenty-two patients with CMV infection after LDLT fulfilled the inclusion criteria and were randomly assigned to the oral VGCV group (n = 11) or the intravenous GCV group (n = 11). Treatment success rates were 82% (9 of 11) and 91% (10 of 11) in the VGCV and GCV groups, respectively. One patient in the VGCV group developed recurrence, whereas no patients in the GCV group developed recurrence. All the patients completed the treatment protocol, and no patients in either group dropped out of the study. In conclusion, oral VGCV and intravenous GCV are safe, feasible options for preemptive treatment of CMV infection after LDLT.

Prophylaxis and Treatment of Cytomegalovirus Infection Postrenal Transplantation in Two Madrid Units

Complete prevention of cytomegalovirus (CMV) disease continues to be an unresolved problem in renal transplantation. From January 2005 to May 2006, we implemented a protocol for early detection and preemptive treatment of CMV infection as detected by antigenemia or polymerase chain reaction determined every 2 weeks during the first 3 months posttransplant and monthly thereafter. Prophylaxis was given to all CMV-negative patients who received CMV-positive kidneys and to those who received polyclonal or monoclonal antibody induction therapy. Among 100 transplants, 15 subjects received prophylaxis due to poly- or monoclonal antibody induction and/or negative recipient serology using a mean valgancyclovir dose of 485 +/- 276 mg/d for an average duration of 129 days. After completion of the prophylaxis four patients (26.6%) required preemptive therapy for asymptomatic virus reactivation; the mean dose of drug in these patients had been 450 +/- 275.56 mg, with a treatment time that was significantly shorter than those not suffering reactivation (91.75 vs 143.45 days). In addition, preemptive therapy was given for virus reactivation in seven patients, for illness with mild viral syndrome in two, with moderate illness and positive pretransplantation serology in one. The average treatment time was 79 days and the mean dose was 375 mg. In those not at risk, CMV infections occurred among 11.7% of patients in our early detection program. Prophylaxis for at-risk patients should continue for more than 3 months to prevent reactivation.

Oral valganciclovir as preemptive therapy for cytomegalovirus infection post allogeneic stem cell transplantation

Antiviral compounds including ganciclovir, foscarnet, and cidofovir are routinely used in the treatment of cytomegalovirus (CMV) infection and disease; however, these agents have a poor oral bioavailability and have the inconvenience and expense of intravenous administration. To evaluate the safety and efficacy of oral valganciclovir (VGCV) for preemptive treatment of CMV reactivation in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). We treated 15 patients receiving allogeneic HSCT from related (n=9) or unrelated (n=6) donors. In all patients, either the donor, host, or both were CMV Ig G positive pretransplant. Indication for therapy was preemptive treatment of CMV infection defined as one or two consecutive positive tests of pp65 antigenemia assay or CMV-polymerase chain reaction (PCR). VGCV was administered orally in a dosage of 900 mg b.i.d. for 2 weeks, followed by 450 mg b.i.d. for 2 additional weeks. Patients developed a positive CMV-PCR after a median of 52 days (range 37-427) post HSCT and a positive pp65 antigenemia after a median time of 74 days (range 37-427) post HSCT. Preemptive treatment with VGCV was started a median time of 56 days (range 37-429) after transplant. In all, 11 patients (73%) completed the 28 days of therapy with VGCV. All patients showed a complete clearance of the virus. The median time to achieve a negative CMV-PCR was 6 days (range 4-18). A relapse of CMV infection after VGCV preemptive therapy occurred in 6 patients (40%). No patient developed early or late CMV disease. Six patients (40%) presented hematological toxicity including neutropenia and/or thrombocytopenia that required drug discontinuation in 4 cases. VGCV administered as preemptive therapy for CMV infection in patients receiving an allogeneic HSCT showed promise for treating this frequent complication. Prospective randomized studies in this setting are mandatory to yield more definitive results.

Valganciclovir Is Safe and Effective as Pre-Emptive Treatment for CMV Infection in Allogeneic Hematopoietic Stem Cell Transplantation.

RATIONALE OF STUDY: Despite significant advances in prevention and therapy, cytomegalovirus (CMV) infection still represents an important cause of morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplant (HSCT). The standard pre-emptive treatment is based on intravenous administration of Ganciclovir (GCV). Valganciclovir (VGC), the pro-drug formulation of GCV is characterised by an excellent bio availability, making this drug suitable for oral administration.PATIENTS: Since March 2003 all patients treated with reduced (27 patients) or fully ablative (3 patients) conditioning regimens followed by sibling HSCT, were monitored with bi-weekly CMV/PCR and pp65/assays. Overall 15 episodes of CMV positivity were detected in seven patients. Patients resulted positive (3 cells pp65+ or 1000/100000 PCR +) started oral treatment with VGC 900 mg bid, for the first fourteen days, followed by 900 mg q.d. up to at least seven days after assays normalization. The median duration of therapy was 21 days (range 10–21 days). No significant toxicity was observed. All patients had a normalization of CMV/PCR and pp65/assays within fourteen days, with a response rate (RR) of 100%. In two patients the oral VGC therapy was changed to the intravenous administration of Foscavir, because of concomitant neutropenia and acute GvHD.CONCLUSION: Pre-emptive treatment of CMV infection with VGC is safe, feasible and effective. Furthermore, the oral administration of this drug in an outpatient setting, reduces significantly the costs compared with a therapy that needs hospitalization as intravenous Ganciclovir.

Long-term prognosis of renal transplantation after preemptive treatment of cytomegalovirus infection.

A role for cytomegalovirus (CMV) infection in the etiologies of acute and chronic rejection in renal allograft recipients has been suggested. We previously reported that preemptive treatment of CMV infection with ganciclovir in kidney transplant patients was safe and effective. We now present a retrospective analysis of 169 consecutive renal transplant patients, of whom 87 (51.5%) received preemptive treatment with ganciclovir (CMV(+) group). No patient died of CMV infection. Actuarial graft and patient survival rates were not different between the CMV(+) and the CMV(-) groups (graft survival: 68% and 69%; patient survival: 89% and 88%, respectively). At the end of the study, the mean plasma creatinine levels were not statistically different between the two groups (185+/-13 and 166+/-12 micromol/L for the CMV(+) group and the CMV(-) group, respectively). These results suggest that preemptive treatment of CMV infection with ganciclovir may prevent the CMV-induced renal injury and graft loss.