Oral Ganciclovir Research Articles

New prophylactic treatment strategy for cytomegalovirus disease.

The pharmacology, pharmacokinetics, safety, and efficacy of valganciclovir, an oral prodrug for ganciclovir, used to prevent cytomegalovirus (CMV) disease in solid organ transplant recipients are described. Valganciclovir was developed to overcome the disadvantages associated with ganciclovir, which include low oral bioavailability, limited efficacy because of the development of viral resistance, and the need for frequent administration, which can adversely affect patient adherence. Valganciclovir is rapidly converted to ganciclovir; systemic exposure to the parent drug is low and short in duration. The oral bioavailability of ganciclovir from valganciclovir is 10 times higher than that from the original ganciclovir formulation. Food increases the oral bioavailability of valganciclovir. In a four-way, randomized, crossover pharmacokinetic study of 28 liver transplant recipients, single doses of valganciclovir 900 mg and intravenous ganciclovir 5 mg/kg resulted in a similar ganciclovir systemic exposure. The systemic exposure was proportionately lower with a single 450-mg dose of valganciclovir but similar to that of oral ganciclovir 3 g administered in three divided doses. In the recent multicenter, randomized, double-blind, double-dummy PV16000 trial in 364 solid organ transplant recipients at high risk for CMV disease (i.e., CMV-negative recipients of CMV-positive donor organs), valganciclovir 900 mg once daily was as effective in preventing CMV-disease as oral ganciclovir 1 g three times daily. Resistance was reported with ganciclovir but not with valganciclovir. Both drugs were well tolerated.

Cost advantages of oral drug therapy for managing cytomegalovirus disease.

Cost advantages of the oral route of drug therapy administration over the intravenous route for managing cytomegalovirus (CMV) disease are described. The overall costs usually are lower for the oral route of administration than for the intravenous route, although the cost to the patient depends on insurance coverage. Other advantages of the oral route include greater safety and convenience, which may improve patient adherence and quality of life. In patients with acquired immunodeficiency syndrome (AIDS), the use of oral ganciclovir instead of intravenous ganciclovir to treat the maintenance phase of CMV retinitis reduced the incidence of neutropenia and sepsis, outpatient and inpatient resource use, and costs. Oral therapy also improved patient quality of life. A cost-effectiveness model for liver transplant recipients found that CMV prophylaxis is warranted for all patients, ganciclovir is preferred over CMV immune globulin i.v. and oral acyclovir for prophylaxis, and the oral route of administration is more cost-effective than the intravenous route for ganciclovir. Valganciclovir, the oral prodrug of ganciclovir, was not included in this model. Oral maintenance therapy is usually cost-effective, safer, and more convenient than intravenous therapy in the management of CMV.

Management of cytomegalovirus infection by weekly surveillance after renal transplant: analysis of cost, rejection and renal function.

Recently published guidelines recommend anti-viral prophylaxis as the best method of preventing cytomegalovirus (CMV) disease in the post-transplant period, but some authors have suggested that surveillance strategies may be as effective and less costly. The aim of the present study was to analyse the effectiveness and cost of a deferred treatment strategy using weekly CMV polymerase chain reaction (PCR) surveillance in high risk renal transplant recipients. We used weekly surveillance for plasma CMV PCR positivity for the first 3 months in consecutive renal transplants between CMV seropositive donors and seronegative recipients, and analysed incidence of CMV infection, timing of infection, acute rejection and renal function at 1 year. There was evidence of CMV infection in 27/41 (65.9%) patients and of CMV disease in 20/41 (48.8%). Only 8/20 (40%) patients were PCR positive before disease onset. Patients were treated on the basis of clinical evidence of CMV disease (deferred strategy), but we used the data to compare the potential costs of a pre-emptive strategy (all patients PCR positive before the onset of clinical features of disease treated with intravenous ganciclovir) and prophylaxis (oral ganciclovir for 3 months in all patients). The deferred strategy cost pound 1159 per patient (excluding the cost of hospitalization) while a pre-emptive strategy would cost pound 1381 per patient. Prophylaxis costs pound 1500- pound 2213 per patient depending on published estimates of relative risk reduction. Mean estimated creatinine clearance at 1 year was 70.0 ml/min in patients who experienced no infection, 47.7 ml/min in patients who experienced infection but no disease, and 39.6 ml/min in patients who experienced CMV disease (P < 0.001). The incidence of acute rejection in these groups was 7.1, 14.3 and 35%, respectively (P = 0.13). CMV surveillance strategies may cost slightly less but may have a deleterious effect on long-term outcome compared with prophylaxis.

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.

Treatment of children with congenital cytomegalovirus infection with ganciclovir

Congenital cytomegalovirus (CMV) infection affects approximately 1% of live births in the US. Ten percent of these infants have symptoms at birth and another 10 to 15% acquire hearing loss or developmental problems. Congenital CMV is the most common cause of nonhereditary sensorineural hearing loss in children, and progressive hearing loss is common. To arrest the natural progression of congenital CMV, children referred to our center were treated with a prolonged course of ganciclovir. Medical records of children with congenital CMV who were treated with ganciclovir were reviewed to tabulate their presenting symptoms, duration of treatment, audiologic and developmental assessments and complications. We treated nine children with symptomatic CMV with iv ganciclovir at a median age of 10 days (range, 3 days to 11 months). Findings at diagnosis included microcephaly (five of nine); petechiae (five of nine); thrombocytopenia (seven of nine); and intracranial calcifications (six of eight). Hearing loss was noted before therapy in five of nine. The median duration of iv and subsequent oral ganciclovir was 1 year and 0.83 year, respectively. Median follow-up was 2 years (range, 1 to 7 years). No child had progression of hearing loss; improvement occurred in two. Seven children had at least one complication of ganciclovir therapy: central venous catheter/site infection (six); catheter malfunction (three); and neutropenia (one). Of nine children none treated with ganciclovir for congenital CMV had detectable progressive hearing loss. Complications associated with iv therapy occurred frequently. Currently available oral analogues of ganciclovir may facilitate earlier and more prolonged therapy for children with symptomatic congenital CMV and should be subjected to randomized controlled trials.

Comparative study of prophylactic oral ganciclovir and valacyclovir in high-risk kidney transplant recipients

Cytomegalovirus (CMV) is a major pathogen in renal transplant patients causing significant post-transplant morbidity and mortality. Prophylactic antiviral therapy, currently implemented in most kidney transplant centres, has significantly reduced the incidence of CMV infection after transplantation. Oral ganciclovir has been shown to be an effective prophylactic agent in preventing CMV disease and infection with a demonstrated superior efficacy over oral acyclovir. Valacyclovir, a prodrug of acyclovir with a higher level of bioavailability than acyclovir, has also been shown to be effective in preventing CMV disease when given as prophylactic treatment. In a retrospective analysis of 150 renal transplant recipients in our centre, we compared the efficacy of oral ganciclovir with valacyclovir in preventing CMV infection. Seventy-seven consecutive renal transplant recipients prophylactically treated with oral ganciclovir for 12 weeks after transplant were compared with 73 consecutive recipients treated with oral valacylovir for an equal length of time. No difference was noted in the incidence of CMV infection between the two treatment groups (5.1 vs 5.4%) after a 6 month follow-up. Likewise, the incidence of acute rejection was similar in both groups (11.6 vs 6.8%). All cases of CMV infection occurred in high-risk patients (donor positive/recipient negative). The prophylactic use of oral valacylovir is as effective as oral ganciclovir in reducing CMV infection and disease after kidney transplantation.

Retinal detachment in cytomegalovirus retinitis: intravenous versus intravitreal therapy

To compare the rate of retinal detachment in a group of patients treated with intravitreal ganciclovir to the rate of retinal detachment in a group of patients treated with systemic ganciclovir. A retrospective non-randomized comparative case series was conducted. The participants were 186 consecutive patients with cytomegalovirus (CMV) retinitis treated at two centres over the period from June 1990 to May 1997. Of the 186, 133 patients had systemic therapy of whom 113 had intravenous ganciclovir or foscarnet and 20 had oral ganciclovir, and 53 patients had intravitreal induction and maintenance therapy. The main outcome measure was the rate of retinal detachment, which was calculated using person-months-at-risk denominators. The effect measure used in the main comparative analysis was the hazard ratio obtained from multiple regression using the Cox proportional hazards model. Retinal detachment occurred in three of 53 patients in the intravitreal therapy group, one of 20 patients receiving oral maintenance therapy and 21 of 113 patients receiving intravenous maintenance therapy. The risk of retinal detachment with systemic therapy was 14-fold higher than with intravitreal therapy (P < 0.001)and up to fourfold higher with oral maintenance therapy. Intravitreal therapy offers a significant advantage over systemic therapy in the treatment of CMV retinitis by substantially reducing the risk of CMV-related retinal detachment.

Cytomegalovirus disease following liver transplantation: an analysis of prophylaxis strategies.

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality following liver transplantation. Though oral ganciclovir may be used as a prophylactic agent, there is some debate as to whether prophylaxis should be given universally or to targeted 'high risk' sub-groups. We, therefore, analysed the cost-effectiveness of both prophylactic strategies. We performed a retrospective cross-sectional study of adult liver transplant (LT) recipients who developed CMV disease in 1997 and estimated the morbidity and costs associated with disease in these patients. These costs were compared with the estimated cost (based on a previous multi-centre study) of using oral ganciclovir prophylaxis in order to assess the potential cost-effectiveness of introducing different prophylactic regimes. Universal and targeted prophylaxis would both have prevented all the likely mortality (2 deaths) from CMV disease in that year. The net cost of applying a targeted prophylaxis strategy would have been 206,275 pounds, (i.e. 103,137 pounds per death avoided). The cost per life year saved would have been 15,674 pounds. We suggest that LT units should identify patients at high risk for the development of CMV disease and adopt a targeted prophylactic strategy.

Oral ganciclovir is more effective than oral aciclovir for long-term prophylaxis of cytomegalovirus (CMV) disease

Oral ganciclovir is more effective than oral aciclovir for long-term prophylaxis of cytomegalovirus (CMV) disease

Cytomegalovirus disease after prophylaxis with oral ganciclovir in renal transplantation: the importance of HLA-DR matching.

This study assessed the incidence of cytomegalovirus (CMV) disease and associated outcomes after oral ganciclovir prophylaxis in renal transplantation. A retrospective analysis was performed of all adult renal transplant recipients at a single transplant center transplanted between August 16, 1996, and December 31, 2000. CMV disease prophylaxis included ganciclovir 1000 mg orally thrice daily prescribed for 90 d in D-/R+ cases and 180 d in D+/R- and D+/R+ cases. Forty (9.1%) of 470 patients studied were diagnosed with CMV disease, which varied significantly by CMV serostatus and number of HLA-DR matches. The highest incidence of disease, 26.2%, was in D+/R- patients with zero HLA-DR matches. Five-year graft survival was 56.8% with CMV disease compared with 79.1% without (P < 0.001). Five-year graft survival with CMV disease was 75.9% with one or two HLA-DR matches versus 16.2% with zero HLA-DR matches (P < 0.001). CMV remains an important factor in long-term graft survival after oral ganciclovir prophylaxis. However, we have observed that the adverse impact of CMV disease on graft survival is apparent only in patients with zero HLA-DR matches. These results call for the development of new CMV disease prophylaxis and treatment strategies in patients with zero HLA-DR matches. In addition, organ allocation policies discouraging combining CMV-seropositive donors and zero HLA-DR matches may be worth consideration.

Discordant phenotypes and genotypes of cytomegalovirus (CMV) in patients with AIDS and relapsing CMV retinitis.

To investigate the correlation between genotypic studies performed on blood leukocytes and phenotypic results obtained from the corresponding blood viral isolates in AIDS patients with relapsing cytomegalovirus (CMV) retinitis. Sequential blood samples were collected from patients failing intravenous or oral ganciclovir therapy. The CMV UL97 gene was amplified directly from leukocyte DNA extracts for assessing the presence of viral mutations using restriction fragment length polymorphism analysis and direct sequencing. Positive viral cultures from the same blood samples were also analyzed for their susceptibility to ganciclovir and their UL97 genotype was determined. Discordant CMV genotypes between the clinical specimen and the viral culture were found in at least one blood sample from three of the four patients with relapsing CMV retinitis. Furthermore, some UL97 mutations at known resistance codons (592, 594) were associated with a drug-susceptible phenotype. In all four cases, genotypic analyses of blood samples better correlated with clinical progression than phenotypic analyses of viral cultures. The presence of mixed viral populations in blood samples of AIDS patients and the potential selection bias introduced by susceptibility testing may underestimate the real impact of CMV resistance in patients failing antiviral therapy.

Randomized controlled trial of oral ganciclovir versus oral acyclovir after induction with intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in cytomegalovirus-seropositive liver transplant recipients

Without effective antiviral prophylaxis, cytomegalovirus (CMV) disease is a common cause of morbidity and mortality after liver transplantation. In this randomized, controlled trial, we compared the efficacy and safety of oral ganciclovir with oral acyclovir after induction with intravenous (IV) ganciclovir for long-term prophylaxis of CMV disease in CMV-seropositive liver transplant recipients. Patients were initially administered IV ganciclovir at a dose of 6 mg/kg per day from day 1 to day 14 after transplantation followed by either oral ganciclovir (1 g every 8 hr) or oral acyclovir (800 mg every 6 hr) from day 15 to day 100 after transplantation. CMV disease occurred in only 1 of 110 patients (0.9%) receiving ganciclovir compared with 8 of 109 patients (7.3%) receiving acyclovir within the first year after transplantation (P =0.019). There was one case of CMV colitis in the ganciclovir group, whereas four cases of CMV syndrome, three cases of CMV pneumonia, and one case of CMV hepatitis developed in the acyclovir group. The only death from CMV disease occurred in an acyclovir-treated patient with CMV pneumonia. Both oral ganciclovir and oral acyclovir were generally well tolerated. Reversible leukopenia (decline in white blood cell count to <3.0 x 10(9)/L) was more common with oral ganciclovir (38/110 patients, 35%) than with oral acyclovir (20/109 patients, 18%) (P =0.009). The emergence of ganciclovir-resistant strains of CMV was not found during the study. A prophylactic regimen of 2 weeks of IV ganciclovir followed by an additional 12 weeks of oral ganciclovir is superior to a similar regimen of IV ganciclovir followed by oral acyclovir and almost completely eliminates CMV disease after liver transplantation. This superior protection against CMV disease extends up to 1 year after transplantation and is not associated with ganciclovir resistance.

DSMB case study:: decision making when a similar clinical trial is stopped early

Two similarly designed, placebo-controlled clinical trials are fully accrued and following patients for safety and outcome data. One trial is stopped at a planned interim analysis by its data safety and monitoring board (DSMB) due to a statistically significant treatment benefit. The statisticians and DSMB of the other trial are informed of these results. What are the responsibilities of the statistical center? How should the DSMB deal with the situation if the data do not support the stopped trial? What should the patients be told concerning the results of the two trials when one trial continues and the other is stopped? This DSMB case study reports on such a situation for two randomized clinical trials of oral ganciclovir for the prevention of cytomegalovirus disease in HIV/AIDS patients.

Intravenous ribavirin : effective therapy for respiratory syncytial virus (RSV) infection after lung transplantation

ents were CMVMM. CMVMM patients surviving 30 days were excluded (n 2). Results: Group 1(n 19) received IV ganciclovir 5mg/kg 3x week for 10 weeks. Group 2(n 7) received IV ganciclovir 5mg/kg BD for 14 days then IV ganciclovir 5mg/kg or oral ganciclovir at 1gm TDS 3x week for a further 10 weeks plus IV CMVIG @ 3x10units on days 1,2,3,7,14,28,56,84. Ref: CMV and Rejection Status Table Conclusion: Prophylatic CMV-IG resulted in a significant reduction in the incidence of rejection within the first 6 months post LTx. However it did not reduce the development of initial CMV disease. Further followup is required to determine long term outcomes, especially recurrence of CMV disease and prevalence of BOS.

Cytomegalovirus infection in solid organ transplantation: economic implications.

Cytomegalovirus (CMV) is a pathogen, commonly encountered in the recipients of solid organ transplantation and is an important cause of morbidity and mortality in these patients. CMV infection and disease have been shown to increase the cost of care in transplant recipients and several different strategies of prevention have been shown to be effective in clinical trials. A systematic review of published information on the economic impact of CMV in solid organ transplantation was performed; both clinical- and decision-analysis-based studies were reviewed. Clinical studies have shown that CMV infection and disease is associated with increased length of hospital stay and overall costs. Decision-analysis-based studies suggest that in general, antiviral chemoprophylaxis against CMV in transplant recipients is a cost-effective intervention compared with other established healthcare interventions such as strategies for colorectal cancer screening. Prophylaxis with oral or parenteral ganciclovir is probably the most cost-effective strategy; however, restricting prophylaxis to high-risk groups (such as donor seropositive/recipient seronegative status and the use of an antilymphocyte antibody) or chemoprophylaxis for an extended period does not improve cost effectiveness. Pre-emptive therapy is an evolving strategy for prevention of CMV disease in transplant recipients and is rapidly gaining in popularity. Well-designed trials incorporating prospective cost data and comparing pre-emptive therapy versus conventional antiviral prophylaxis are needed to establish the superiority of one strategy over the other.

Prevention of Human Immunodeficiency Virus–Related Opportunistic Infections in France: A Cost‐Effectiveness Analysis

A simulation model of human immunodeficiency virus (HIV) disease, which incorporated French data on the progression of HIV disease in the absence of antiretroviral therapy and on cost, was used to determine the clinical impact and cost-effectiveness of different strategies for the prevention of opportunistic infections in French patients who receive highly active antiretroviral therapy (HAART). Compared with use of no prophylaxis, use of trimethoprim-sulfamethoxazole (TMP-SMZ) increased per-person lifetime costs from euro 185,600 to euro 187,900 and quality-adjusted life expectancy from 112.2 to 113.7 months, for an incremental cost-effectiveness ratio of euro 18,700 per quality-adjusted life-year (euro/QALY) gained. Compared with use of TMP-SMZ alone, use of TMP-SMZ plus azithromycin cost euro 23,900/QALY gained; adding fluconazole cost an additional euro 54,500/QALY gained. All strategies that included oral ganciclovir had cost-effectiveness ratios that exceeded euro 100,000/QALY gained. In the era of HAART, on the basis of French data, prophylaxis against Pneumocystis carinii pneumonia, toxoplasmic encephalitis, and Mycobacterium avium complex bacteremia is cost-effective. Prophylaxis against fungal and cytomegalovirus infections is less cost-effective than are other therapeutic options for HIV disease and should remain of lower priority.

Pre-emptive oral ganciclovir can reduce the risk of cytomegalovirus disease in liver transplant recipients

A cohort of 65 liver transplant recipients was prospectively monitored with qualitative polymerase chain reaction (PCR) in plasma. The first 25 patients did not receive prophylaxis. From a consecutive group of 40 recipients, 11 high-risk patients donor CMV-seropositive/receptor CMV-seronegative (D+/R–), persistent CMV replication) received pre-emptive oral ganciclovir (1000 mg three times daily), when a marker of risk was identified, until day 90. The overall incidence of cytomegalovirus (CMV) disease at six months was 20% (five of 25 patients) in the non-prophylaxis group and 2.5% (one of 40 patients) in the group treated with pre-emptive oral ganciclovir (relative risk, 0.11; 95% confidence interval; 0.01–0.96; P = 0.04). The PCR sensitivity for detecting CMV disease was 80%, the specificity was 90%, and the positive and negative predictive values were 66% and 95%, respectively. Adverse events, graft rejection and survival were similar between groups. We conclude that pre-emptive oral ganciclovir in high-risk patients can reduce the risk of CMV disease.

A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation

A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation

Stratégies de prévention des infections à CMV chez les sujets immunodéprimés

Cytomegalovirus (CMV) infection in immunosuppressed patients is associated with mortality if treatment is not prescribed. Strategies for the prevention of CMV disease is very important to establish. The choice of a strategy depends on epidemiologic factors (CMV-positivity of the patient or of the donor if transplantation), on the type of immunosuppression (allogeneic bone marrow transplantation, solid organ transplantation, HIV infected patients, long-term corticosteroid therapy). Several strategies for prevention can be proposed : prophylaxis for all patients, prophylaxis only for patients at high-risk, preemptive therapy when antigenemia or PCR (leucocytes or plasma) are positive, secondary prophylaxis. A treatment is proposed, except for CMV-negative patient, and CMV-negative donor if transplantation. It can be intravenous and/or oral ganciclovir, intravenous acyclovir or oral valaciclovir. Valganciclovir is an oral prodrug of ganciclovir that can be used in HIV patients with CMV disease. The strategy employed must have the better efficacy but quality of life and cost-effectivness have to be considered. Clinical evaluation is useful to determine the more adapted strategy.

Treatment of Active Cytomegalovirus Disease with Oral Ganciclovir in Renal Allograft Recipients: Monitoring Efficacy with Quantitative Cytomegalovirus Polymerase Chain Reaction

Treatment regimens of patients with active cytomegalovirus (CMV) disease require 2-3 weeks of intravenous ganciclovir (GCV) with/without CMV hyperimmune globulin. Oral GCV is effective as a prophylactic agent in prevention of CMV disease. Here we explored the utility of oral GCV as a treatment of active CMV disease. Fifteen renal allograft recipients (CMV donor+/recipient- [53%], CMV donor+/recipient+ [40%] or CMV donor-/recipient+ [7%]) developed active CMV disease. Cytomegalovirus polymerase chain reaction (CMV-PCR) tests were performed at the time of presentation and patients were treated with oral ganciclovir 1 g tid (adjusted for renal function). Patients were monitored for efficacy of treatment by assessment of clinical symptoms and CMV-PCR. Treatment was continued until the CMV-PCR copy number was negative and symptoms resolved. The mean CMV-PCR copy number at the time of diagnosis was 580 copies/microg DNA (nl: < 5 copies/microg DNA). After 5-7 days of treatment, the mean copy number was 65 copies/microg DNA. Fourteen of 15 patients responded well to oral ganciclovir, with complete resolution of clinical symptoms and eradication of CMV-PCR positivity. One patient did not respond to oral ganciclovir therapy due to probable noncompliance. Our data suggest that oral ganciclovir treatment, coupled with careful CMV-PCR monitoring, may be a reasonable alternative to long-term intravenous ganciclovir.