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American Journal of Transplantation :... Jun 2010In 2001 valganciclovir was approved by the FDA for treatment of HIV associated retinitis and in 2003 for prevention of post transplant CMV. This review provides an... (Review)
Review
In 2001 valganciclovir was approved by the FDA for treatment of HIV associated retinitis and in 2003 for prevention of post transplant CMV. This review provides an update on the status of its use and areas of controversy: How long should prophylaxis be given?; What is the appropriate dose for prophylaxis?; Can it be used in children, and at what dose?; Can it be used to treat CMV disease? The question of optimal dosing will probably not be settled as the sample size for controlled trials would be prohibitive. Other trials clearly show that extended therapy provides added benefit, the drug is safe and an appropriate dose has been identified in children and oral therapy of CMV disease is effective.
Topics: Administration, Oral; Child; Clinical Trials as Topic; Ganciclovir; HIV Seropositivity; Humans; Valganciclovir
PubMed: 20455881
DOI: 10.1111/j.1600-6143.2010.03112.x -
Current Opinion in Oncology Sep 2012The discovery of Kaposi sarcoma herpesvirus (KSHV) led to recognition of KSHV-associated multicentric Castleman disease (MCD) as a distinct lymphoproliferative disorder.... (Review)
Review
PURPOSE OF REVIEW
The discovery of Kaposi sarcoma herpesvirus (KSHV) led to recognition of KSHV-associated multicentric Castleman disease (MCD) as a distinct lymphoproliferative disorder. The pathogenesis of KSHV-MCD is attributed to proliferation of KSHV-infected B cells, production of KSHV-encoded viral interleukin 6 by these cells, and dysregulation of human interleukin 6 and interleukin 10. This article reviews advances in the field of disease pathogenesis and targeted therapies.
RECENT FINDINGS
Our understanding of the pathogenesis of KSHV-MCD has increased in recent years and improved therapies have been developed. Recent studies demonstrate that the anti-CD20 monoclonal antibody, rituximab, as well as virus-activated cytotoxic therapy using high-dose zidovudine and valganciclovir, can control symptoms and decrease adenopathy. With treatment, 1-year survival now exceeds 85%. Interestingly, even in the absence of pathologic findings of MCD, KSHV-infected patients may have inflammatory symptoms, excess cytokine production, and elevated KSHV viral load similar to KSHV-associated MCD. The term KSHV-associated inflammatory cytokine syndrome has been proposed to describe such patients.
SUMMARY
Recent advances in targeted therapy have improved outcomes in KSHV-MCD, and decreased need for cytotoxic chemotherapy. Improved understanding of the pathogenesis of KSHV-MCD and KSHV-associated inflammatory cytokine syndrome is needed, and will likely lead to additional advances in therapy for these disorders.
Topics: Antibodies, Monoclonal, Murine-Derived; Antiviral Agents; Castleman Disease; Ganciclovir; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Rituximab; Valganciclovir; Zidovudine
PubMed: 22729151
DOI: 10.1097/CCO.0b013e328355e0f3 -
Transplant Infectious Disease : An... Jun 2010In an open-label, prospective, pharmacokinetic assessment, we evaluated total drug exposure (area under the curve [AUC]) of intravenous (IV) ganciclovir (GCV) and oral... (Clinical Trial)
Clinical Trial
In an open-label, prospective, pharmacokinetic assessment, we evaluated total drug exposure (area under the curve [AUC]) of intravenous (IV) ganciclovir (GCV) and oral (p.o.) valganciclovir when normalized for body surface area (BSA) in pediatric liver (n=20) and renal (n=26) transplant patients Reference doses for IV GCV (200 mg/m(2)) and p.o. valganciclovir (520 mg/m(2)) were based on adult doses, and adjusted for BSA initially, and BSA and renal function (estimated via creatinine clearance [CrCL]) thereafter. Renal transplant patients received GCV on days 1-2, valganciclovir 260 mg/m(2) on day 3, and valganciclovir 520 mg/m(2) on day 4. Liver transplant patients received twice daily GCV from enrollment to day 12, and then valganciclovir twice daily on days 13-14. GCV pharmacokinetics were described using a population pharmacokinetic approach. Type of solid organ transplant (kidney or liver) had no effect on GCV pharmacokinetics. Median GCV exposure following valganciclovir 520 mg/m(2) was similar to that with IV GCV, and to that reported in adults. Patients <5 years of age had AUC values approximately 50% of those compared with older age ranges; dosing based on both BSA and CrCL increased drug exposure in younger patients. A dosing algorithm based on BSA and CrCL should be tested in future studies.
Topics: Administration, Oral; Adolescent; Adult; Algorithms; Antiviral Agents; Area Under Curve; Body Surface Area; Child; Child, Preschool; Creatinine; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Female; Ganciclovir; Humans; Infant; Injections, Intravenous; Kidney Transplantation; Liver Transplantation; Male; Valganciclovir; Young Adult
PubMed: 20002356
DOI: 10.1111/j.1399-3062.2009.00478.x -
World Journal of Gastroenterology Aug 2014Cytomegalovirus (CMV) infection is a common complication after liver transplantation, and it is associated with multiple direct and indirect effects. Management of CMV... (Review)
Review
Cytomegalovirus (CMV) infection is a common complication after liver transplantation, and it is associated with multiple direct and indirect effects. Management of CMV infection and disease has evolved over the years, and clinical guidelines have been recently updated. Universal antiviral prophylaxis and a pre-emptive treatment strategy are options for prevention. A currently-recruiting randomized clinical trial is comparing the efficacy and safety of the two prevention strategies in the highest risk D+R- liver recipients. Drug-resistant CMV infection remains uncommon but is now increasing in incidence. This highlights the currently limited therapeutic options, and the need for novel drug discoveries. Immunotherapy and antiviral drugs with novel mechanisms of action are being investigated, including letermovir (AIC246) and brincidofovir (CMX001). This article reviews the current state of CMV management after liver transplantation, including the updated practice guidelines, and summarizes the data on investigational drugs and vaccines in clinical development.
Topics: Antiviral Agents; Cytomegalovirus Infections; Humans; Liver Transplantation; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 25152570
DOI: 10.3748/wjg.v20.i31.10658 -
American Journal of Transplantation :... Oct 2008The precise impact of valganciclovir as preventive therapy for cytomegalovirus (CMV) in solid organ transplant (SOT) recipients is not fully defined. Data from studies... (Review)
Review
The precise impact of valganciclovir as preventive therapy for cytomegalovirus (CMV) in solid organ transplant (SOT) recipients is not fully defined. Data from studies using valganciclovir as preemptive therapy or prophylaxis for CMV in SOT recipients were synthesized for descriptive analysis. CMV disease occurred in 2.6% and 9.9% of the patients receiving valganciclovir as preemptive therapy and prophylaxis, respectively. Although the incidence of early-onset (
valganciclovir prophylaxis, the incidence of late-onset (>90 days posttransplant) CMV disease rose up to 8.9% and 17.7% in the prophylactic group, respectively. On the contrary, no patients developed late-onset CMV disease in preemptive group. Both approaches with valganciclovir have successfully decreased CMV disease in SOT recipients. Late-onset CMV disease is a complication observed uniquely with valganciclovir prophylaxis, particularly in R-/D+ patients, but not with preemptive therapy. Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Kidney Diseases; Kidney Transplantation; Liver Diseases; Liver Transplantation; Risk; Time Factors; Transplantation Immunology; Treatment Outcome; Valganciclovir; Virology
PubMed: 18828771
DOI: 10.1111/j.1600-6143.2008.02369.x -
Antibiotics (Basel, Switzerland) Jan 2021Valganciclovir (VGCV) and ganciclovir (GCV) doses must be adjusted according to indication, renal function and weight. No specific therapeutic exposure values have been...
Valganciclovir (VGCV) and ganciclovir (GCV) doses must be adjusted according to indication, renal function and weight. No specific therapeutic exposure values have been established. We aimed to evaluate the adequacy of VGCV/GCV doses, to assess the interpatient variability in GCV serum levels, to identify predictive factors for this variability and to assess the clinical impact. This is a prospective study at a tertiary institution including hospitalized patients receiving VGCV/GCV prophylaxis or treatment. Adequacy of the antiviral dose was defined according to cytomegalovirus guidelines. Serum levels were determined using High-Performance Liquid Chromatography. Blood samples were drawn at least 3 days after antiviral initiation. Outcome was considered favorable if there was no evidence of cytomegalovirus infection during prophylaxis or when a clinical and microbiological resolution was attained within 21 days of treatment and no need for drug discontinuation due to toxicity. Seventy consecutive patients [74.3% male/median age: 59.2 years] were included. VGCV was used in 25 patients (35.7%) and GCV in 45 (64.3%). VGCV/GCV initial dosage was deemed adequate in 47/70 cases (67.1%), lower than recommended in 7/70 (10%) and higher in 16/70 (22.9%). Large inter-individual variability of serum levels was observed, with median trough levels of 2.3 mg/L and median peak levels of 7.8 mg/L. Inadequate dosing of VGCV/GCV and peak levels lower than 8.37 or greater than 11.86 mg/L were related to poor outcome. Further studies must be performed to confirm these results and to conclusively establish if VGCV/GCV therapeutic drug monitoring could be useful to improve outcomes in specific clinical situations.
PubMed: 33467490
DOI: 10.3390/antibiotics10010077 -
The Journal of Pediatrics May 2024To assess the efficacy of valganciclovir in infants with hearing loss and clinically inapparent congenital cytomegalovirus infection (cCMV), as there is no consensus on...
OBJECTIVE
To assess the efficacy of valganciclovir in infants with hearing loss and clinically inapparent congenital cytomegalovirus infection (cCMV), as there is no consensus on treatment of this group.
STUDY DESIGN
A nationwide, nonrandomized controlled trial, comparing 6 weeks of oral valganciclovir to no treatment in infants with cCMV, recruited after newborn hearing screening resulted in referral to an audiologist. The choice whether to treat was left to parents of subjects. Eligible subjects were full term infants aged <13 weeks with sensorineural hearing loss and diagnosed with cCMV through dried blood spot testing. The primary outcome, measured by linear and ordinal logistic regression, was change in best-ear hearing from baseline to follow-up at 18-22 months of age.
RESULTS
Thirty-seven participants were included in the final analysis, of whom 25 were in the treatment group and 12 in the control group. The majority of subjects in both groups had neuroimaging abnormalities, which were mostly mild. Hearing deterioration was more likely in the control group compared with the treatment group (common OR 0.10, 95% CI 0.02-0.45, P = .003). Mean best-ear hearing deteriorated by 13.7 dB in the control group, compared with improvement of 3.3 dB in the treatment group (difference 17 dB, 95% CI 2.6 - 31.4, P = .02).
CONCLUSIONS
We investigated treatment in children with hearing loss and clinically inapparent cCMV. Although our study was nonrandomized, it is the first prospective and controlled trial in this population. Valganciclovir-treated children with hearing loss and inapparent cCMV had less hearing deterioration at 18 through 22 months of age than control subjects.
EUDRACT REGISTRY NUMBER
2013-003068-30.
Topics: Humans; Valganciclovir; Cytomegalovirus Infections; Antiviral Agents; Male; Female; Infant; Infant, Newborn; Hearing Loss, Sensorineural; Treatment Outcome; Ganciclovir; Neonatal Screening; Prospective Studies; Follow-Up Studies; Administration, Oral
PubMed: 38336204
DOI: 10.1016/j.jpeds.2024.113945 -
The Pediatric Infectious Disease Journal Jun 2019Congenital cytomegalovirus infections are among the most common of the newborn in the developed world. These infections are the most common cause of sensorineural... (Review)
Review
Congenital cytomegalovirus infections are among the most common of the newborn in the developed world. These infections are the most common cause of sensorineural hearing loss. Studies utilizing ganciclovir and valganciclovir demonstrate improved hearing and Bailey Developmental scores. Because of the ease of administration, valganciclovir is the recommended treatment of choice for 6 months. Therapy should be reserved for those babies with symptomatic disease; no data are available regarding the impact of treatment on those babies with asymptomatic disease.
Topics: Antiviral Agents; Clinical Trials as Topic; Cytomegalovirus Infections; Ganciclovir; Hearing Loss, Sensorineural; Herpes Simplex; Humans; Infant, Newborn; Infant, Newborn, Diseases; Valganciclovir
PubMed: 31205247
DOI: 10.1097/INF.0000000000002325 -
Transplant International : Official... Dec 2015Cytomegalovirus is the most important pathogen causing opportunistic infections in kidney allograft recipients. The occurrence of CMV disease is associated with higher... (Review)
Review
Cytomegalovirus is the most important pathogen causing opportunistic infections in kidney allograft recipients. The occurrence of CMV disease is associated with higher morbidity, higher incidence of other opportunistic infections, allograft loss and death. Therefore, an efficient strategy to prevent CMV disease after kidney transplantation is required. Two options are currently available: pre-emptive therapy based on regular CMV PCR monitoring and generalized antiviral prophylaxis during a defined period. In this review, we describe those two approaches, highlight the distinct advantages and risks of each strategy and summarize the four randomized controlled trials performed in this field so far. Taken this evidence together, pre-emptive therapy and anti-CMV prophylaxis are both equally potent in preventing CMV-associated complications; however, the pre-emptive approach may have distinct advantages in allowing for development of long-term anti-CMV immunity. We propose a risk-adapted use of these approaches based on serostatus, immunosuppressive therapy and availability of resources at a particular transplant centre.
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Kidney Transplantation; Opportunistic Infections; Post-Exposure Prophylaxis; Pre-Exposure Prophylaxis; Randomized Controlled Trials as Topic; Transplantation, Homologous; Valganciclovir
PubMed: 26138458
DOI: 10.1111/tri.12629 -
World Journal of Hepatology Jun 2014Cytomegalovirus (CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and... (Review)
Review
Cytomegalovirus (CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and occasional mortality. CMV causes febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted liver allograft. In addition, CMV has been significantly 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. To negate the adverse effects of CMV infection on transplant outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component to the management of liver transplant recipients. Two recently updated guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and such occurrence of late-onset CMV disease was significantly associated with increased all-cause and infection-related mortality after liver transplantation. Therefore, a search for better strategies for prevention, such as prolonged duration of antiviral prophylaxis, a hybrid approach (antiviral prophylaxis followed by preemptive therapy), or the use of immunologic measures to guide antiviral prophylaxis has been suggested to prevent late-onset CMV disease. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, reduction in pharmacologic immunosuppression. In one clinical trial, oral valganciclovir was as effective as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. The aim of this article is to provide a state-of-the art review of the epidemiology, diagnosis, prevention, and treatment of CMV infection and disease after liver transplantation.
PubMed: 25018848
DOI: 10.4254/wjh.v6.i6.370