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Transplantation May 2018The VIPP study compared valganciclovir prophylaxis with preemptive treatment regarding efficacy, safety, and long-term graft outcome in cytomegalovirus (CMV)-positive... (Comparative Study)
Comparative Study Randomized Controlled Trial
Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: Long-term Results After 7 Years of a Randomized Clinical Trial.
BACKGROUND
The VIPP study compared valganciclovir prophylaxis with preemptive treatment regarding efficacy, safety, and long-term graft outcome in cytomegalovirus (CMV)-positive (R+) renal transplant recipients.
METHODS
Multicenter, open-label, randomized clinical study with a 12-month study phase and a follow-up of up to 84 months. Patients in the prophylaxis group received 2 × 450 mg/d oral valganciclovir for 100 days adjusted to renal function. Preemptive treatment with 2 × 900 mg/d valganciclovir was initiated at a viral load of 400 CMV copies/mL or greater (polymerase chain reaction) and maintained over ≥14 days, followed by secondary prophylaxis. Patients were stratified by donor CMV IgG serostatus (donor CMV IgG positive [D+]/R+, donor CMV IgG negative [D-]/R+).
RESULTS
The 12-month results were reported previously (Witzke et al Transplantation 2012). The intent-to-treat/safety population comprised 148 patients in the prophylaxis (61.5% D+/R+) and 151 patients in the preemptive group (52.3% D+/R+). Overall, 47% patients completed the follow-up. Significantly fewer patients in the prophylaxis compared with preemptive group experienced a CMV infection or disease up to month 84 (11.5%; 95% confidence interval [95% CI], 6.8-17.8%] vs 39.7%; 95% CI, 31.9-48.0%; P < 0.0001 and 4.7%; 95% CI, 1.9-9.5% vs 15.9%; 95% CI, 10.5-22.7%; P = 0.002). Incidences of graft loss (7.4% vs 8.6%), death (9.5% vs 11.3%), rejection (29.1% vs 28.5%), and renal function (estimated glomerular filtration rate [mean ± SD]: 58.2 ± 26.3 vs 59.9 ± 25.7 mL/min per 1.73 m) were not significantly different between prophylaxis and preemptive treatment. Tolerability was comparable between groups.
CONCLUSIONS
Prophylaxis was more effective than the preemptive approach, applying a low-intense surveillance protocol in preventing CMV infection and disease in intermediate-risk patients. Both strategies were similarly effective in preventing graft loss and death under the conditions of this long-term trial with a threshold of 400 copies/mL for initiation of anti-CMV treatment.
Topics: Adult; Aged; Allografts; Antiviral Agents; Austria; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Drug Administration Schedule; Female; Germany; Graft Survival; Humans; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome; Valganciclovir; Viral Load; Young Adult
PubMed: 29166336
DOI: 10.1097/TP.0000000000002024 -
Neuro-oncology Mar 2014
Topics: Antineoplastic Agents; Antiviral Agents; Brain Neoplasms; Cytomegalovirus Infections; Ganciclovir; Glioblastoma; Humans; Valganciclovir
PubMed: 24523452
DOI: 10.1093/neuonc/nou011 -
Neuro-oncology Jul 2019Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to...
BACKGROUND
Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy.
METHODS
Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed.
RESULTS
TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy.
CONCLUSION
Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy.
Topics: Adenoviridae; Animals; Antiviral Agents; Apoptosis; Cell Proliferation; Genetic Therapy; Genetic Vectors; Glioblastoma; Humans; Mice; Neoplasm Invasiveness; Prodrugs; Simplexvirus; Thymidine Kinase; Tumor Cells, Cultured; Valganciclovir; Xenograft Model Antitumor Assays
PubMed: 30958558
DOI: 10.1093/neuonc/noz060 -
Microbiology and Immunology Apr 2022This study aimed to compare the efficacy of valaciclovir, valganciclovir, and artesunate in treating chronic reactivated human herpesvirus type 6 (HHV-6) and human...
A comparative study of valaciclovir, valganciclovir, and artesunate efficacy in reactivated HHV-6 and HHV-7 infections associated with chronic fatigue syndrome/myalgic encephalomyelitis.
This study aimed to compare the efficacy of valaciclovir, valganciclovir, and artesunate in treating chronic reactivated human herpesvirus type 6 (HHV-6) and human herpesvirus type 7 (HHV-7) infection associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). From 255 patients (192 cases) with reactivated HHV-6 and HHV-7 infections (confirmed based on blood leukocyte PCR), valaciclovir, valganciclovir, or artesunate was administered at a dose of 3000, 900, and 100 mg/day, respectively, for 3 months (study group). The control group consisted of similar patients with ME/CFS (n = 63) not taking any antiviral drugs. The significance of differences was evaluated by Student's t-test and the nonparametric criterion-the number of Z-signs. Negative PCR results in patients with HHV-6 and HHV-7 treated with valaciclovir was achieved in 26% and 23% (first month), 34%, and 28% (second month), 37% and 34% of cases (third month), respectively (P < 0.05; Z < Z ). The same results with valganciclovir were obtained in 35% and 33% (first month), 44% and 39% (second month), 48% and 45% of cases (third month), but with artesunate in 44% and 41% (first month), 57% and 53% (second month), 68% and 63% of cases (third month), respectively (P < 0.05; Z < Z ). Artesunate is more effective than valganciclovir and valacyclovir in patients with ME/CFS with reactivated HHV-6 and HHV-7 infections.
Topics: Artesunate; Fatigue Syndrome, Chronic; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Valacyclovir; Valganciclovir
PubMed: 35102619
DOI: 10.1111/1348-0421.12966 -
Transplant Infectious Disease : An... Jun 2020Few data support use of 6 over 3 months of antiviral prophylaxis for cytomegalovirus (CMV) disease prevention in donor seropositive/recipient seronegative (D+R-) heart...
BACKGROUND
Few data support use of 6 over 3 months of antiviral prophylaxis for cytomegalovirus (CMV) disease prevention in donor seropositive/recipient seronegative (D+R-) heart transplant recipients (HTR).
METHODS
We retrospectively assessed CMV disease and outcomes in 310 adult HTR between July 5, 2005, and December 30, 2016, at our center. Valganciclovir (VGCV) prophylaxis was given for 3-6 months in the D+R- group. Multivariable models evaluated risk factors for CMV disease in patients who received 3 vs 6 months (±1 month) of prophylaxis, with investigation of inverse probability weighting to correct for confounding variables.
RESULTS
The incidence of CMV disease among all patients and the D+R- group was 8.7% (27/310) and 26.5% (22/83), respectively, and included syndrome in 22.2% (6/27) and end-organ involvement in 77.8% (21/27). In a multivariable model, 6 vs 3 months of antiviral prophylaxis was not associated with reduced risk for CMV disease (OR 2.28 [95% CI 0.66, 7.91], P = .19). CMV disease in D+R- HTR was associated with higher rates of hospitalization (87.5% [14/16] vs 6.3% [1/16], P < .001) and for a longer duration than in matched D+R- controls without disease.
CONCLUSIONS
Cytomegalovirus disease remains a major cause of morbidity in D+R- HTR. In contrast to documented benefit in D+R- lung and kidney recipients, VGCV duration of 6 months was not associated with a lower incidence of CMV disease in D+R- HTR compared to 3-month duration and should be reconsidered in this patient population.
Topics: Antiviral Agents; Cytomegalovirus Infections; Female; Heart Transplantation; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Risk Factors; Tissue Donors; Transplant Recipients; Valganciclovir
PubMed: 32020736
DOI: 10.1111/tid.13255 -
Seminars in Nephrology Sep 2016Cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7 are ubiquitous β-herpesviruses that can cause opportunistic infection and disease in kidney transplant... (Review)
Review
Cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7 are ubiquitous β-herpesviruses that can cause opportunistic infection and disease in kidney transplant recipients. Active CMV infection and disease are associated with acute allograft failure and death, and HHV-6 and HHV-7 replication are associated with CMV disease. CMV prevention strategies are used commonly after kidney transplantation, and include prophylaxis with antiviral medications and preemptive treatment upon the detection of asymptomatic viral replication in blood. Both approaches decrease CMV disease and allograft rejection, but CMV prophylaxis is preferred for high-risk patients because it is easy to administer and may be more effective in real-world settings. CMV disease commonly occurs even with current preventive strategies, whereas HHV-6 and HHV-7 diseases are rare. The clinical manifestations of CMV, HHV-6, and HHV-7 are nonspecific, and laboratory confirmation is essential to establishing diagnoses. Although nucleic acid testing has supplanted other diagnostic modalities given its high sensitivity and specificity, histopathologic examination sometimes is necessary to identify disease definitively. Ganciclovir and valganciclovir are the treatments of choice for CMV and HHV-6, and foscarnet can be used to treat HHV-7. Treatment duration should be informed by the initial severity of disease, and subsequent clinical and virologic responses.
Topics: Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Graft Rejection; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Roseolovirus Infections; Valganciclovir
PubMed: 27772620
DOI: 10.1016/j.semnephrol.2016.05.012 -
Polski Merkuriusz Lekarski : Organ... Jul 2013Cytomegalovirus infection is particularly dangerous for patients undergoing solid organs transplantation. Among these patients cytomegalovirus disease (CMV) may occur.... (Review)
Review
UNLABELLED
Cytomegalovirus infection is particularly dangerous for patients undergoing solid organs transplantation. Among these patients cytomegalovirus disease (CMV) may occur. CMV disease is associated with increased mortality, organ damage and reduced graft survival. THE AIM OF THE STUDY was to determine the clinical outcomes (clinical efficacy and safety profile) for the use of valganciclovir administered for 200 days compared to standard period of 100 days in the prevention of cytomegalovirus disease in seronegative patients after kidney transplantation from infected donor (high risk patients).
MATERIAL AND METHODS
A systematic review of literature published during the period: 1st January 1966-31st October 2010, was performed in order to assess the efficacy and safety of valganciclovir in the treatment of cytomegalovirus disease. Databases MEDLINE (PubMed), EMBASE and Cochrane were searched.
RESULTS
A systematic review yielded 1 randomized and 3 nonrandomized clinical trials. 200 days prophylaxis with valganciclovir significantly decreased a risk of: cytomegalovirus disease, CMV viral load, opportunistic infections; percentage of patients with high viral load was also significantly decreased compared to 100 days therapy. The safety profile of extended therapy was similar to that observed within 100 days prophylaxis. The higher risk of leucopenia in the 200 days than 100 days group was the only one adverse event that met statistical significance. The results of non-randomized trials were comparable to those mentioned above.
CONCLUSION
Prolonged prophylaxis of cytomegalovirus till 200 days in high-risk patients (D+/B-) is safe and provides significant therapeutic benefits.
Topics: Antiviral Agents; Cytomegalovirus Infections; Drug Administration Schedule; Ganciclovir; Graft Survival; Humans; Kidney Transplantation; Treatment Outcome; Valganciclovir; Viral Load
PubMed: 23984598
DOI: No ID Found -
Pediatric Transplantation Mar 2024Valganciclovir is approved for cytomegalovirus prophylaxis in pediatrics using the Pescovitz algorithm. There are reports of valganciclovir overdoses in children with...
BACKGROUND
Valganciclovir is approved for cytomegalovirus prophylaxis in pediatrics using the Pescovitz algorithm. There are reports of valganciclovir overdoses in children with low body surface area and overestimated creatinine clearance utilizing this algorithm. This study compared the incidence of neutropenia and cytomegalovirus infection between the Pescovitz and weight-based dosing algorithms.
METHODS
A single-center retrospective chart review from January 2010 to September 2018 was performed on pediatric heart, liver, and kidney transplant recipients, who received valganciclovir. Data were collected from the initiation of valganciclovir prophylaxis to 30 days after discontinuation. The primary objective was the incidence of neutropenia in patients receiving valganciclovir dosed by the Pescovitz versus weight-based dosing algorithms.
RESULTS
This study included 187 pediatric transplant recipients who received valganciclovir dosed via the Pescovitz (62 recipients) or weight-based dosing algorithms (125 recipients). The incidence of neutropenia was higher in the Pescovitz (69.4%) compared to the weight-based dosing group (53.6%; p = .04) including moderate and severe neutropenia. Cytomegalovirus viremia was not significantly different between the two groups and occurred in 4.8% of the Pescovitz group compared to 2.4% of the weight-based group (p = .4).
CONCLUSIONS
The incidence of neutropenia was greater in recipients receiving valganciclovir dosed via the Pescovitz algorithm compared to the weight-based dosing. There were no significant differences in regard to cytomegalovirus viremia or disease between the two groups.
Topics: Humans; Child; Valganciclovir; Antiviral Agents; Retrospective Studies; Transplant Recipients; Cytomegalovirus Infections; Neutropenia; Organ Transplantation; Viremia; Ganciclovir
PubMed: 38420722
DOI: 10.1111/petr.14714 -
Archives of Disease in Childhood Jul 2022Ganciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However,... (Observational Study)
Observational Study
BACKGROUND
Ganciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However, this treatment may have the potential to induce mitochondrial toxicity due to off-target inhibition of DNA-polymerases. Similar anti-HIV drugs have been associated with mitochondrial toxicity but this has never been explored in CMV.
OBJECTIVE
To determine the potential mitochondrial toxicity profile at the genetic, functional and biogenesis level in peripheral blood mononuclear cells from a cohort of newborns and infants with symptomatic congenital CMV infection (treated with valganciclovir, untreated and uninfected controls).
DESIGN
Longitudinal, observational and controlled study.
SETTING AND PATIENTS
Subjects were recruited at the tertiary referral Hospital Sant Joan de Déu and experiments were conducted at IDIBAPS-Hospital Clínic of Barcelona, Spain. CMV-infected newborns underwent comprehensive monthly clinical follow-up.
METHODS
Mitochondrial parameters, audiometry and neurological assessment were measured at baseline, 3-6 and 12 months after inclusion in the study. The Kruskal-Wallis test for k-independent samples and Friedman tests for repeated measurements were applied.
RESULTS
Complex IV, citrate synthase enzymatic activities and mtDNA remained preserved in congenital CMV-infected infants treated with valganciclovir compared with controls (p>0.05 in all cases).
CONCLUSIONS
No evidence of mitochondrial toxicity was found in infants treated with valganciclovir for congenital CMV.
Topics: Anti-HIV Agents; Antiviral Agents; Child; Cytomegalovirus Infections; Ganciclovir; Humans; Infant; Infant, Newborn; Leukocytes, Mononuclear; Longitudinal Studies; Valganciclovir
PubMed: 35288419
DOI: 10.1136/archdischild-2021-322996 -
Clinical Transplantation Oct 2023Cytomegalovirus (CMV) is a common infection in abdominal transplant recipients (ATR). Prevention of CMV in the highest risk population (CMV IgG donor+/recipient-) is...
BACKGROUND
Cytomegalovirus (CMV) is a common infection in abdominal transplant recipients (ATR). Prevention of CMV in the highest risk population (CMV IgG donor+/recipient-) is critical as CMV is associated with negative outcomes. Guideline recommended prophylactic valganciclovir dosing is 900 mg daily for 6 months in this population. However, reduced dosing strategies are utilized in practice.
METHODS
This single center, retrospective study in adult ATR compared full valganciclovir prophylactic dosing (900 mg daily for 6 months) to reduced dosing (900 mg daily for 3 months, then 450 mg daily for 3 months). The primary endpoint was incidence of CMV infection with viral load >1000 IU/mL. Secondary endpoints included incidence of CMV infection with viral load 200-1000 IU/mL, neutropenia, and leukopenia.
RESULTS
Incidence of CMV infection with viral load >1000 IU/mL (29% vs. 27%, p = 1) or CMV infection with viral load 200-1000 IU/mL (6% vs. 12%, p = .421) did not differ significantly between 68 ATR in reduced and full dosing groups, as well as incidence of leukopenia (94% vs. 97%, p = 1) and neutropenia (77% vs. 70%, p = .586).
CONCLUSIONS
There was no difference in the incidence of CMV infection, neutropenia, or leukopenia of the two dosing regimens, although time to CMV diagnosis was different.
Topics: Adult; Humans; Valganciclovir; Cytomegalovirus; Antiviral Agents; Ganciclovir; Retrospective Studies; Transplant Recipients; Cytomegalovirus Infections; Neutropenia
PubMed: 37256906
DOI: 10.1111/ctr.15041