Treatment Of Cytomegalovirus Disease Research Articles

Protein kinase inhibitors of the quinazoline class exert anti-cytomegaloviral activity in vitro and in vivo

Cytomegalovirus infection is associated with severe disease in immunocompromised individuals. Current antiviral therapy faces several limitations. In a search of novel drug candidates, we describe here the anti-cytomegaloviral properties of two compounds of the chemical class of quinazolines, gefitinib (Iressa ®) and Ax7396 (RGB-315389). Both compounds showed strong inhibitory effects in vitro against human and animal cytomegaloviruses with IC 50s in a low micromolar range. Cytotoxicity did not occur at these effective concentrations. The antiviral mode of action was based on the inhibition of protein kinase activity, mainly directed to a viral target kinase (UL97/M97) in addition to cellular target candidates. This was demonstrated by a high sensitivity of the respective protein kinases in vitro and by infection experiments with viral mutants carrying genomic alterations in the ORF UL97/M97 modulating viral drug sensitivity. In a guinea pig model, gefitinib showed inhibition of cytomegaloviral loads in blood and lung tissue. Importantly, the rate of mortality of infected animals was reduced by gefitinib treatment. In contrast to the in vitro data, Ax7396 showed no significant antiviral activity in a mouse model. Further in vivo analyses have to assess the potential use of gefitinib in the treatment of cytomegalovirus disease.

Use of Valganciclovir for Prevention and Treatment of Cytomegalovirus Disease

The development of a valine ester for ganciclovir has allowed much-improved absorption and bioavailability of oral ganciclovir and has had a significant impact on the prevention and management of cytomegalovirus infection in the immunocompromised host. Valganciclovir offers ~60% bioavailability after oral ingestion. The administration of 900 mg of valganciclovir orally is comparable to a dose of intravenous ganciclovir of 5 mg/kg, although the peak level of ganciclovir is higher than that of oral valganciclovir [ 1 ] . Given this comparability, the use of valganciclovir for preemptive therapy and even for treatment of cytomegalovirus is becoming quite common, even with limited comparative trial data [2]. The article by Len et al [3] from the Spanish Network for Research on Infection in Transplantation (RESITRA) in this issue of Clinical Infectious Diseases reports an observational study that offers some insight into the efficacy of valganciclovir for the prevention and treatment of cytomegalovirus disease. Although this study d sign is not as rigorous as a randomized trial, and although it was subject to some investigator and clinician bias in patient selection, the data are nevertheless compelli g and demonstrate that valganciclovir can be used for preemptive therapy for cy omegalovirus infection in organ transplant recipients [3]. The definitions of success and failure in this study are rigorous, and the number of patients studied was large. Once viral replication was established, it is quite clear that valganciclovir is effective for viral suppression, to prevent progression to cytomegalovirus syndrome or organ disease. The vast majority of the data in this study derive from kidney and liver transplant recipients (and, to a lesser extent, from heart transplant patients); therefore, generalizability of the results to lung or kidney-pancreas transplant recipients is probably not justified. Furthermore, the data provide a limited experience regarding the cytomegalovirus antibody-negative recipients of transplants from antibody-positive donors, who represent the highestrisk group for late-onset and relapse. Thus, additional studies are required for these groups to provide information for such use. However, I think transplant programs can feel confident that the use of valganciclovir for preemptive therapy has merit for the vast majority of organ transplant recipients. In many programs, it is already the standard of care for either prophylaxis or preemptive therapy. Although the US Food and Drug Administration has cautioned against the use of valganciclovir for prevention of cytomegalovirus infection in liver transplant recipients [4], the data here support its use and also are consistent with what many liver transplantation programs are actually using as their protocol. The data from this Spanish group are not as compelling regarding the use of valganciclovir for treatment of invasive cytomegalovirus disease, which they label disease in tables 2 and 3 of their article [3]. The success rate of 75% is less than the success rate for intravenous ganciclovir (87.5%) or intravenous ganciclovir followed by valganciclovir (96.2%). Although the difference was not statistically significant, only 8 patients with focal were treated exclusively with valganciclovir. Although there were only 2 treatment failures, I believe that more experience will be necessary to conclude that valganciclovir therapy is appropriate initial management of tissue invasive disease. The authors do not indicate the lo-

Valganciclovir as Treatment for Cytomegalovirus Disease in Solid Organ Transplant Recipients

Cytomegalovirus (CMV) infection causes morbidity in solid organ transplant (SOT) recipients, either by direct injury or in association with chronic allograft rejection or other opportunistic infections. Ganciclovir is the treatment of choice, but this agent requires intravenous administration, which affects its feasibility for long-term use. Valganciclovir, which has an oral bioavailability of 60%, has proven to be useful for prophylaxis of CMV infection in high-risk SOT recipients and for treating retinitis in persons with acquired immunodeficiency syndrome. To compare the efficacy of valganciclovir (alone or as sequential therapy after a regimen of intravenous ganciclovir) with intravenous ganciclovir alone for preemptive therapy or treatment of CMV disease (viral syndrome or focal disease) in SOT recipients and to determine the incidence of adverse effects and relapses. In this 2-year prospective, comparative cohort study, 376 episodes of preemptive therapy or treatment of CMV disease were recorded among 334 of 3467 SOT recipients included in the Spanish Network for Research on Infection in Transplantation (RESITRA) database. Intravenous ganciclovir was the first-line treatment in 170 episodes; valganciclovir followed by intravenous ganciclovir was administered in 82 episodes, and valganciclovir alone was administered in 112 episodes. Valganciclovir was used as preemptive therapy or treatment for CMV disease in 84 and 28 episodes, respectively. Duration of treatment was longer in valganciclovir recipients than in ganciclovir recipients for both preemptive therapy (21 vs. 15 days; P < .001) or viral syndrome treatment (21 vs. 18 days; P < .01). In the valganciclovir arm, 94 (83.9%) of 112 episodes were treated successfully, with no statistical difference in the success rates versus the ganciclovir arm (85.8%) or ganciclovir-valganciclovir arm (95.1%). Eighteen episodes (16.1%) treated with valganciclovir were considered to have resulted in treatment failure (because of persistent antigenemia in 4 [3.6%], on the basis of clinical decision in 7 [6.2%], and because of recurrent disease in 7 [6.2%]). There were no incidents in which valganciclovir treatment was withdrawn because of toxicity. Valganciclovir is safe and useful for preemptive therapy and treatment of CMV disease.

Cytomegalovirus infection after liver transplantation: Current concepts and challenges

Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D+/R- serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4+ and CD8+ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-). However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D+/R- liver transplant recipients. Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being performed comparing the efficacy and safety of maribavir, a novel benzimidazole riboside, and oral ganciclovir as prophylaxis against primary CMV disease in liver transplant recipients. The treatment of CMV disease consists mainly of intravenous (IV) ganciclovir, and if feasible, a reduction in the degree of immunosuppression. A recent controlled clinical trial demonstrated that valganciclovir is as effective and safe as IV ganciclovir for the treatment of CMV disease in solid organ (including liver) transplant recipients. In this article, the author reviews the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.

Prophylaxis and treatment of cytomegalovirus disease in recipients of solid organ transplants: current approach and future challenges

Cytomegalovirus infection is a major cause of morbidity and mortality in solid-organ transplant recipients, in terms of cytomegalovirus disease itself and the associated outcomes of organ rejection and death. This review focuses on recent literature concerning prevention and treatment of cytomegalovirus disease in this population. Two major strategies for the prevention of cytomegalovirus infection in solid-organ transplant recipients - preemptive and prophylactic treatment - are reviewed. Both strategies result in a lower incidence of cytomegalovirus disease when compared to a 'wait and treat' approach, and are generally considered cost-effective. Neither prophylaxis nor preemption has yet been shown to be superior. Newer trials are also reviewed, which are beginning to evaluate protocols of preemption or prophylaxis representative of current practice, as well as to explore alternative dosing strategies, the benefits of cytomegalovirus immune globulin, and the potential benefit of a longer course of prophylaxis. Concerns for the selection of ganciclovir-resistant strains of cytomegalovirus are also addressed. The consensus is that there is benefit for the treatment of solid-organ transplant patients with an antiviral agent before clinical evidence of cytomegalovirus disease. So far, there has been no demonstration of the superiority of prophylactic or preemptive regimens, nor has the exact nature and dosing of the oral antiviral agent of choice been established.

Prevention and management of cytomegalovirus infection in solid-organ transplantation

Cytomegalovirus (CMV) is the most common opportunistic viral infection to occur following solid-organ transplantation. This review will discuss the current strategies of management of CMV in solid-organ transplantation and their challenges. There are two principal approaches for preventing CMV disease in recipients of solid-organ transplants: prophylactic and pre-emptive. Ganciclovir is the most studied and used antiviral for both treatment and prevention, and is the first-line treatment for CMV infection and CMV disease in transplant recipients. There is no consensus regarding the most appropriate prevention method and the approach to CMV disease prevention differs among transplantation centers owing to the paucity of data comparing the two strategies head-to-head. Currently, the recommended treatment for CMV disease is intravenous ganciclovir.

Efficacy of Valganciclovir in the Treatment of Cytomegalovirus Disease in Kidney and Pancreas Transplant Recipients

Cytomegalovirus (CMV) disease is relatively common following solid organ transplant, particularly if a serologically negative recipient receives an organ from a serologically positive donor (D +/R −). Although valganciclovir is approved for the treatment of CMV retinitis in AIDS patients and is used for the prophylaxis against CMV infection in solid organ transplant patients, the current standard treatment for CMV disease in solid organ transplant recipients remains intravenous ganciclovir. We retrospectively reviewed our experience using valganciclovir as treatment for CMV disease in CMV D +/R − kidney and/or pancreas transplant recipients from March 2002 to June 2005. A total of 37 cases with primary CMV disease were diagnosed and treated with either intravenous ganciclovir as induction followed with valganciclovir or valganciclovir from the beginning. We compared clinical outcomes and viremia between the two groups. Our data suggest that valganciclovir is an effective treatment modality for primary CMV disease in kidney and/or pancreas transplant recipients. It led to the resolution of disease and undetectable viremia. Valganciclovir allowed for early initiation of treatment and for treatment to be given as an outpatient. These advantages of valganciclovir have both health and economic impact for patients with CMV disease.

Treatment of multidrug‐resistant cytomegalovirus retinitis with systemically administered leflunomide

Multiresistant cytomegalovirus (CMV) infection is increasingly recognized in solid organ transplant recipients. Leflunomide is a novel drug with both immunosuppressive and anti-CMV properties. Herein we report a case of a renal transplant recipient treated with leflunomide for multiresistant CMV retinitis, and provide correlation between serum and vitreous levels of leflunomide. She had stabilization of her retinitis and measurable levels of drug in her vitreous fluid and serum. These initial findings suggest that leflunomide may be useful in the treatment of CMV disease, including retinitis in patients after solid organ transplantation.

A Prospective Evaluation of Leflunomide Therapy for Cytomegalovirus Disease in Renal Transplant Recipients

Aim A preliminary observation suggests leflunomide is effective in the treatment of cytomegalovirus (CMV) disease in renal transplant recipients. A prospective evaluation was conducted in renal transplant recipients to study the efficacy of leflunomide in the treatment of CMV disease. Patients and methods With prior approval and informed consent for therapy and follow-up, 17 consecutive consenting renal transplant recipients with proven CMV disease were treated with leflunomide. CMV disease was defined as a clinical syndrome of fever and/or symptoms of organ involvement, leukopenia, and a positive nested CMV quantitative PCR test at 0.001 μg/5 μL template input, with or without histologic evidence of tissue invasion. Leflunomide metabolite concentrations (A77 1726) were monitored. Results Of the 17 patients, 14 patients were treated for 6 months for CMV disease the first time; the remaining 3 received leflunomide treatment for relapse after ganciclovir treatment, for a year. Seven patients had fever with viremia and no organ involvement, nine had viremia with involvement of gastrointestinal tract, and one had fever with CMV inclusions in the allograft, with no demonstrable viremia. The three patients with relapse treated with leflunomide responded. Overall, 15 patients (88%) clinically responded to leflunomide therapy and with viral clearance from blood and healing of involved organs. The cost of therapy with intravenous ganciclovir (Cymevene, Roche) for 2 weeks was US $721 while that of leflunomide (Cleft, Cipla Ltd) for 6 months was US $64. Conclusion Leflunomide treatment for CMV disease in renal transplant recipients is effective, simple, and economical.

Quantitative PCR in the diagnosis of CMV infection and in the monitoring of viral load during the antiviral treatment in renal transplant patients

Cytomegalovirus (CMV) infection is a significant problem in transplantation. In this study, a quantitative PCR test was compared with the CMVpp65 antigenemia assay not only in the diagnosis CMV infections but especially in the monitoring of viral loads during ganciclovir treatment of CMV disease in individual renal transplant patients. Altogether 342 blood specimens were obtained from 116 patients. Blood specimens were used for Cobas Amplicor Monitor plasma PCR and for the pp65 assay. Also shell vial culture was performed. The patients with a positive pp65 finding were monitored for CMV weekly during ganciclovir treatment and/or until the antigenemia subsided. CMV was detected in 31/116 (27%) patients, of whom 14 (12%) developed CMV disease and were treated with ganciclovir. CMV was found by shell vial culture in 13/14 cases, but by PCR and pp65 test in all 14 patients. CMV was detected in 156 (45%) samples; by PCR in 121/156 (range 344-103,000 copies/ml) and by pp65 test in 138/156 (range 1-1,000 positive cells/50,000 leukocytes) and by culture in 59/156 (38%) only. The peak viral loads were significantly (P<0.0001) higher in CMV disease than in untreated infections (19,650 vs. 379 copies/ml, and 100 vs. 5pp65 positive cells). In the monitoring of individual patients, the time-related CMV-DNAemia and pp65 antigenemia correlated well during the treatment of CMV disease. In conclusion, Cobas Amplicor Monitor plasma PCR and CMVpp65 antigen assays can be equally used in the diagnosis CMV infection and in the monitoring of viral load during antiviral treatment.

The CARI guidelines. CMV disease and kidney transplant: treatment of cytomegalovirus disease in renal transplant recipients.

The CARI guidelines. CMV disease and kidney transplant: treatment of cytomegalovirus disease in renal transplant recipients.

The CARI guidelines. CMV disease and kidney transplant: prophylaxis for cytomegalovirus infection in patients following renal transplantation.

The CARI guidelines. CMV disease and kidney transplant: prophylaxis for cytomegalovirus infection in patients following renal transplantation.

Hypogammaglobulinemia after heart transplantation: use of intravenous immunoglobulin replacement therapy in relapsing CMV disease

Secondary hypogammaglobulinemia after heart transplantation may follow immunosuppressive therapy with the resultant increased risk of infections, including cytomegalovirus (CMV) disease. There is limited information on the use of intravenous immunoglobulin replacement therapy (IVIG) in heart-transplanted patients with hypogammaglobulinemia and CMV disease. We present data on five consecutive heart-transplanted patients with relapsing CMV disease, four of whom developed gastrointestinal disease. The immunosuppressive regimen included prednisone, cyclosporine A, azathioprine, mycophenolate mofetil, tacrolimus and antithymocyte globulin (ATG). Evaluation revealed CMV antigenemia. All the patients had been treated with intravenous ganciclovir. In addition, hyperimmune CMV immunoglobulin was administered in three patients. Significantly reduced levels of immunoglobulin G (IgG) were observed in the patients as compared with 15 heart-transplanted individuals without CMV disease [mean IgG levels: 323±18 and 639±63 mg/dl, respectively ( p=0.003)]. IVIG [FLEBOGAMMA], 200–400 mg/kg every 21 days with the goal of maintaining normal serum IgG levels, was added for the treatment of CMV disease. Selected batches with the highest anti-CMV titers were set apart for the treatment of the patients. IVIG treatment, in combination with antiviral therapy, proved able to control CMV disease. There was a favorable clinical response and the patients became free of gastrointestinal symptoms. Detection of CMV antigens was negative after treatment. During IVIG therapy no immediate or delayed adverse effects were observed. Even if our survey was limited to five cases, the results suggest that addition of IVIG to antiviral chemotherapy might improve outcome in heart-transplanted patients with hypogammaglobulinemia and CMV disease.

The CARI guidelines. CMV disease and kidney transplant: pre-emptive treatment of cytomegalovirus.

The CARI guidelines. CMV disease and kidney transplant: pre-emptive treatment of cytomegalovirus.

Treatment of cytomegalovirus disease with valganciclovir in renal transplant recipients: a single center experience.

Recent data suggest valganciclovir (VGC) to be as effective as ganciclovir for cytomegalovirus (CMV) prophylaxis. The objective of this study was to analyze the effect of oral valganciclovir in renal transplant patients with symptomatic CMV infection. Twenty-one patients with symptomatic CMV infection received VGC in doses adjusted to renal function until resolution of CMV antigenemia. The patients were followed for a mean of 5.5 months. During therapy, CMV antigenemia dropped in all patients from pretreatment positive levels of 5.2 +/- 3.7 to negative values of 0.25 +/- 0.2 positive cells/10,000 PBMC (P<0.001). After cessation of therapy, none of patients developed relapse of CMV antigenemia/symptoms within the follow-up. VGC therapy was well tolerated in all patients and no major adverse effects occurred. This pilot trial showed VGC to be safe and highly effective in antiviral therapy after renal transplantation. However, subsequent multicenter clinical trials for treatment of CMV disease are necessary.

A case of arthritis caused by cytomegalovirus after kidney transplantation

Cytomegalovirus (CMV) is the leading cause of infectious complications after organ transplantation. We report the case of a 55-year-old renal transplant recipient who presented with CMV infection 2 months after transplantation. During oral ganciclovir treatment (5 weeks after interruption of intravenous ganciclovir), he experienced a sharp pain in the right shoulder. Examination was normal, but CMV antigenemia remained positive with 30 cells/300,000. He underwent a shoulder puncture, which confirmed the presence of CMV in the articular fluid after evaluation by polymerase chain reaction gene amplification. The patient recovered from his arthritis of the shoulder, and antigenemia became negative after 3 weeks of parenteral ganciclovir. We describe a CMV arthritis that occurred despite a curative treatment for CMV disease, and comment on the pathogenesis of this infection, the pharmalogical failure, and dosing or treatment duration.

Valganciclovir for the prevention and treatment of cytomegalovirus disease in immunocompromised hosts

Valganciclovir (Valcyte®, Roche), a prodrug of the deoxyguanosine analog ganciclovir (Cytovene®, Roche), is indicated for induction and maintenance treatment of cytomegalovirus retinitis in patients with AIDS and for prevention of cytomegalovirus disease in selected high-risk solid organ transplant recipients. After oral administration, valganciclovir is rapidly absorbed and converted to ganciclovir by intestinal and hepatic esterases. Valganciclovir is a highly recognized substrate of the intestinal peptide transporter PEPT1, which underlies the tenfold higher bioavailability of ganciclovir after valganciclovir compared to oral ganciclovir administration. At oral dose of 900 mg, valganciclovir provides a systemic ganciclovir exposure that is comparable to intravenous ganciclovir, at the standard dose of 5 mg/kg of body weight. Subsequent phosphorylation of ganciclovir, which occurs preferentially within cytomegalovirus-infected cells, results in the active metabolite, ganciclovir triphosphate, which is responsible for suppressing viral DNA synthesis by competitively inhibiting the incorporation of the natural substrate deoxyguanosine into viral DNA and thereby, terminating cytomegalovirus replication.

Prevention and treatment of cytomegalovirus disease in solid organ transplant recipients: The clinical and economic impact of evolving strategies: Introduction

Journal Article Prevention and treatment of cytomegalovirus disease in solid organ transplant recipients: The clinical and economic impact of evolving strategies: Introduction Get access Mark D. Pescovitz, M.D. Mark D. Pescovitz, M.D. Professor of Surgery, Microbiology Immunology and Director of the Organ Transplant Program, Indiana University Medical Center, Indianapolis, IN Address correspondence to Dr. Pescovitz at the Indiana University, RM UH 4258, 550 University Boulevard, Indianapolis, IN 46202 mpescov@iupui.edu. Search for other works by this author on: Oxford Academic Google Scholar American Journal of Health-System Pharmacy, Volume 60, Issue suppl_8, 1 December 2003, Pages S3–S4, https://doi.org/10.1093/ajhp/60.suppl_8.S3 Published: 01 December 2003

Prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplants.

The main risk factors for cytomegalovirus (CMV) disease in recipients of allogeneic stem cell transplants (SCT) are recipient CMV seropositivity and acute graft-versus-host disease. Currently, two antiviral strategies, prophylactic or preemptive antiviral treatment, are used for prevention of CMV disease. Preemptive treatment is most favorable when short-term (14-day) treatment is applied. Several methods are available for monitoring of CMV reactivation. PCR-based CMV DNA detection assays are the most sensitive methods; however, the clinical benefit of this high sensitivity is unclear. Even more, there is lack of clarity whether PCR tests can better be performed with plasma, whole blood, or peripheral blood leukocyte samples. Recovery of a CMV-specific CD8(+) cytotoxic-T-lymphocyte (CTL) response is necessary for preventing CMV reactivation and disease. Reconstitution of absolute CMV-specific CTL counts to values above 10 x 10(6) to 20 x 10(6) CTLs/liter is associated with protection from CMV disease. In the near future, preemptive therapy might be withheld in patients with CMV reactivation who are shown to have adequate CMV-specific cytotoxic T-cell levels. Antiviral therapy with (val)acyclovir has been studied only as prophylactic treatment for prevention of CMV infection. High-dose oral valacyclovir is more effective than acyclovir when used in addition to preemptive treatment of CMV reactivation with ganciclovir or foscarnet. Three antiviral drugs have been tested for preemptive therapy of CMV reactivation and/or treatment of CMV disease. Although intravenous ganciclovir is considered the drug of choice, foscarnet has similar efficacy and less toxicity, especially hematologic toxicity. Cidofovir has not been tested extensively, but so far the results are disappointing. Oral valganciclovir for preemptive treatment of SCT recipients is currently being studied. In addition to antiviral therapy, adoptive immunotherapy with CMV-specific cytotoxic T cells as prophylactic or preemptive therapy is a very elegant strategy; however, generation of these cells is expensive and time-consuming, and therefore the therapy is not available at every transplantation center. Magnetic selection of CMV-specific CD8(+) T cells from peripheral blood by using HLA class I-peptide tetramers may be very promising, making this strategy more accessible.

Cytomegalovirus Infection

Cytomegalovirus Infection