Treating HIV-associated cytomegalovirus retinitis with oral valganciclovir and intra-ocular ganciclovir by primary HIV clinicians in southern Myanmar: a retrospective analysis of routinely collected data.

Authors: Jillian Murray, Adelene Hilbig, Theint Thida Soe...

BACKGROUND

Cytomegalovirus retinitis (CMVR) is an opportunistic infection in HIV-infected people. Intraocular or intravenous ganciclovir was gold standard for treatment; however, oral valganciclovir replaced this in high-income countries. Low- and middle-income countries (LMIC) frequently use intraocular injection of ganciclovir (IOG) alone because of cost.

METHODS

Retrospective review of all HIV-positive patients with CMVR from February 2013 to April 2017 at a Médecins Sans Frontièrs HIV clinic in Myanmar. Treatment was classified as local (IOG) or systemic (valganciclovir, or valganciclovir and IOG). The primary outcome was change in visual acuity (VA) post-treatment. Mortality was a secondary outcome.

RESULTS

Fifty-three patients were included. Baseline VA was available for 103 (97%) patient eyes. Active CMVR was present in 72 (68%) eyes. Post-treatment, seven (13%) patients had improvement in VA, 30 (57%) had no change, and three (6%) deteriorated. Among patients receiving systemic therapy, four (12.5%) died, compared with five (24%) receiving local therapy (p = 0.19).

CONCLUSIONS

Our results from the first introduction of valganciclovir for CMVR in LMIC show encouraging effectiveness and safety in patients with advanced HIV. We urge HIV programmes to include valganciclovir as an essential medicine, and to include CMVR screening and treatment in the package of advanced HIV care.

Topics: AIDS-Related Opportunistic Infections; Administration, Oral; Adult; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Retinitis; Female; Ganciclovir; HIV; Humans; Injections, Intraocular; Male; Middle Aged; Myanmar; Primary Health Care; Retrospective Studies; Treatment Outcome; Valganciclovir; Visual Acuity

PubMed: 33187478
DOI: 10.1186/s12879-020-05579-2

Randomized Controlled Trial

Authors: Timothy S Blackwell, Justin C Hewlett, Wendi R Mason...

Human herpesviruses Epstein-Barr virus and cytomegalovirus are frequently detectable in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and could contribute to disease pathogenesis. With the goal of inhibiting herpesvirus replication, we tested the safety and tolerability of adding valganciclovir to standard IPF therapy (pirfenidone). We performed a single-center, Phase I, double-blind, randomized, placebo-controlled trial comparing valganciclovir 900 mg daily with placebo in patients with IPF with serologic evidence of prior Epstein-Barr virus and/or cytomegalovirus infection who were tolerating full-dose pirfenidone (2,403 mg/d). Subjects were randomized to valganciclovir or placebo 2:1 for 12 weeks of active treatment with off-treatment follow-up for up to 12 months. The primary safety endpoint was the number of subjects discontinuing the study drug before completing 12 weeks of treatment. Thirty-one subjects with IPF were randomized to valganciclovir ( = 20) or placebo ( = 11). All subjects completed assigned therapy except one subject in the valganciclovir group, who discontinued the study drug after developing a rash. The total number of adverse events was similar between study groups. In a prespecified analysis of secondary physiologic endpoints, we observed a trend toward improved forced vital capacity from randomization to Week 12 in valganciclovir-treated subjects (-10 ml; interquartile range [IQR], -65 to 70 ml) versus placebo-treated subjects (40 ml; IQR, -130 to 60 ml), which persisted through 12 months of follow-up. Valganciclovir is safe and well tolerated as an add-on therapy to pirfenidone in patients with IPF. Clinical trial registered with ClinicalTrials.gov (NCT02871401).

Topics: Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Idiopathic Pulmonary Fibrosis; Valganciclovir; Vital Capacity

PubMed: 33740394
DOI: 10.1513/AnnalsATS.202102-108OC

Authors: Alejandro Ferrer-Machín, Martín Vera-Cabrera, Inmaculada Plasencia-García...

OBJECTIVE

Immunosuppressive drugs are necessary to avoid or reduce the risk of rejection of transplanted organs. The immunosuppression generated may result in these patients needing  antibiotics and antivirals to be prescribed to them in conjunction with their immunosuppressants to avoid the risk of infection. This has generated an increase in neutropenia in patients treated with mycophenolate mofetil in combination with valganciclovir. The purpose of this study is to estimate the risk of neutropenia attributable to combination treatment of mycophenolate mofetil with valganciclovir in patients with a transplanted liver.

METHOD

This is a retrospective cohort study. It included patients who received a liver transplant between 2012 and 2017 and who were treated with mycophenolate mofetil or with a combination of mycophenolate mofetil and valganciclovir. Minimum follow-up was 100 days posttransplantation. Children under 16 years of age and patients who died during follow-up were excluded. Binary logistic regression analysis was used to determine the association of neutropenia with sex, age, diabetes, creatinine at baseline and at discharge, and concomitant treatment of mycophenolate mofetil with valganciclovir. Relative risk and 95% CI were calculated using logistic regression coefficients.

RESULTS

144 patients were analyzed, 87 were treated with mycophenolate mofetil and 57 received mycophenolate mofetil and valganciclovir together. An overall risk of neutropenia of 37% [95% CI (29- 45)] was observed. The risk was significantly higher in patients who received the combination of mycophenolate mofetil and valganciclovir (56%) than in those treated with mycophenolate mofetil alone (24%), p = 0.001. Binarylogistic-regression analysis revealed that concomitant use of mycophenolate mofetil with valganciclovir was associated with an increased risk of neutropenia: Relative risk = 4.97, 95% CI [2.25-11.00].

CONCLUSIONS

Our study shows that concomitant use of mycophenolate mofetil and valganciclovir increases the risk of neutropenia in patients with a transplanted liver.

Topics: Child; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Neutropenia; Retrospective Studies; Valganciclovir

PubMed: 33709891
DOI: 10.7399/fh.11571

Authors: Yu-Chun Cheng, Eugene Yu-Chuan Kang, Yih-Shiou Hwang...

We evaluated the therapeutic outcome of intravitreal injection (IVI) of ganciclovir with/without oral valganciclovir for cytomegalovirus (CMV) anterior segment infection. We enrolled 61 patients (61 eyes) with PCR-proven CMV anterior segment infection. IVI of ganciclovir (2 mg/0.05 mL) was given as a loading dose; subsequent use of oral valganciclovir (900 mg twice daily) was determined according to the severity of anterior chamber inflammation after injection. All eyes had IVI of ganciclovir, and 53 patients received oral valganciclovir as adjunctive therapy with a mean duration of 1.9 months to achieve disease remission. Repeated diagnostic aqueous taps were performed in 37 eyes with suspected recurrence, and CMV DNA was positive in 24 eyes. This therapeutic strategy afforded a median 50% recurrence-free survival time of 47.0 ± 8.12 months. The patients' mean best corrected visual acuity, intraocular pressure and corneal endothelial cell counts stabilized or improved. Corneal transplantation before CMV infection diagnosis was identified as an independent risk factor for recurrence (hazard ratio 6.81, 95% confidence interval 1.21-38.23, P = 0.029). In patients with CMV anterior segment infection, the relative short-term therapeutic strategy, IVI of ganciclovir in adjunction with/without oral valganciclovir, effectively achieved a median recurrence-free survival time of nearly 4 years.

Topics: Administration, Oral; Adult; Aged; Anterior Chamber; Antiviral Agents; Cornea; Corneal Edema; Corneal Transplantation; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Drug Administration Schedule; Female; Ganciclovir; Humans; Intraocular Pressure; Intravitreal Injections; Male; Middle Aged; Pseudophakia; Recurrence; Retrospective Studies; Risk Factors; Treatment Outcome; Valganciclovir; Visual Acuity

PubMed: 33542372
DOI: 10.1038/s41598-021-82637-y

Observational Study

Authors: Alba Ortiz-Gracia, María Ríos, Ester Tobías...

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

Authors: Francesca Garofoli, Giuseppina Lombardi, Micol Angelini...

Ganciclovir and its prodrug valganciclovir are elective treatments for cCMV. Neonates with important symptoms undergo 6 months of therapy to ameliorate/prevent symptoms and late sequelae, but evidence of resistance is emerging. Over the last 5 years, we took care of 59 cCMV infants and experienced two cases of resistance among nine cCMV infants receiving long-term valganciclovir therapy. In the first case, valganciclovir therapy was prolonged beyond 6 months due to severity of symptoms, control of viral load, and absence of adverse events. Resistance was detected in the 8th month of therapy. In the second case, after a significant reduction following valganciclovir administration and no adverse events, CMV viral load suddenly increased in the 6th month of therapy due to resistance. Both events were associated with UL97 gene mutation. The cCMV infants, affected by severe symptoms, remained in a steady state during treatment, and their later neurological development was coherent with initial seriousness of diagnosis. Prolonged therapeutic exposure may therefore be a risk for resistance, suggesting that constant dosage/weight adjustments, monthly surveillance of viral load, and therapeutic drug monitoring could be proposed to monitor resistance onset and optimize the therapy regime. The risk-benefit ratio for long-term therapy, including the possibility of resistance onset, alongside SNHL and neurodevelopmental improvement, should also be evaluated.

Topics: Adult; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Female; Ganciclovir; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Mutation; Valganciclovir; Viral Load

PubMed: 32615325
DOI: 10.1016/j.ijid.2020.06.087

Authors: Jessica Leung, Sheila C Dollard, Scott D Grosse...

PURPOSE

The aim of this study was to assess the clinical characteristics and trends in valganciclovir use among infants diagnosed with congenital cytomegalovirus (CMV) disease in the United States.

METHODS

We analyzed data from medical claims dated 2009-2015 from the Truven Health MarketScan Commercial Claims and Encounters and Medicaid databases. We identified infants with a live birth code in the first claim who were continuously enrolled for at least 45 days. Among infants diagnosed with congenital CMV disease, identified by an ICD-9-CM or ICD-10-CM code for congenital CMV infection or CMV disease within 45 days of birth, we assessed data from claims containing codes for any CMV-associated clinical condition within the same period, and data from claims for hearing loss and/or valganciclovir within the first 180 days of life.

FINDINGS

In the commercial and Medicaid databases, we identified 257 (2.5/10,000) and 445 (3.3/10,000) infants, respectively, diagnosed with congenital CMV disease, among whom 135 (53%) and 282 (63%) had ≥1 CMV-associated condition, 30 (12%) and 32 (7%) had hearing loss, and 41 (16%) and 78 (18%) had a claim for valganciclovir. Among infants with congenital CMV disease who had a claim for valganciclovir, 37 (90%) among commercially insured infants and 68 (87%) among Medicaid-insured infants had ≥1 CMV-associated condition and/or hearing loss. From 2009 to 2015, the percentages with a claim for valganciclovir increased from 0% to 29% among commercially insured infants and from 4% to 37% among Medicaid-insured infants (P < 0.0001).

IMPLICATIONS

During 2009-2015, there was a strong upward trend in valganciclovir claims among insured infants who were diagnosed with congenital CMV disease, the majority of whom had CMV-associated conditions and/or hearing loss.

Topics: Antiviral Agents; Cytomegalovirus Infections; Databases, Factual; Female; Hearing Loss, Sensorineural; Humans; Infant; Infant, Newborn; International Classification of Diseases; Male; Medicaid; United States; Valganciclovir

PubMed: 29397198
DOI: 10.1016/j.clinthera.2018.01.006

Randomized Controlled Trial

Less renal allograft fibrosis with valganciclovir prophylaxis for cytomegalovirus compared to high-dose valacyclovir: a parallel group, open-label, randomized controlled trial.

Authors: Tomas Reischig, Martin Kacer, Petra Hruba...

BACKGROUND

Cytomegalovirus (CMV) prophylaxis may prevent CMV indirect effects in renal transplant recipients. This study aimed to compare the efficacy of valganciclovir and valacyclovir prophylaxis for CMV after renal transplantation with the focus on chronic histologic damage within the graft.

METHODS

From November 2007 through April 2012, adult renal transplant recipients were randomized, in an open-label, single-center study, at a 1:1 ratio to 3-month prophylaxis with valganciclovir (n = 60) or valacyclovir (n = 59). The primary endpoint was moderate-to-severe interstitial fibrosis and tubular atrophy assessed by protocol biopsy at 3 years evaluated by a single pathologist blinded to the study group. The analysis was conducted in an intention-to-treat population.

RESULTS

Among the 101 patients who had a protocol biopsy specimen available, the risk of moderate-to-severe interstitial fibrosis and tubular atrophy was significantly lower in those treated with valganciclovir (22% versus 34%; adjusted odds ratio, 0.31; 95% confidence interval, 0.11-0.90; P = 0.032 by multivariate logistic regression). The incidence of CMV disease (9% versus 2%; P = 0.115) and CMV DNAemia (36% versus 42%; P = 0.361) were not different at 3 years.

CONCLUSIONS

Valganciclovir prophylaxis, as compared with valacyclovir, was associated with a reduced risk of moderate-to-severe interstitial fibrosis and tubular atrophy in patients after renal transplantation.

TRIAL REGISTRATION

Australian New Zealand Clinical Trials Registry ( ACTRN12610000016033 ). Registered on September 26, 2007.

Topics: Adult; Antibiotic Prophylaxis; Antiviral Agents; Australia; Cytomegalovirus; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Female; Fibrosis; Graft Survival; Humans; Incidence; Intention to Treat Analysis; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Transplantation, Homologous; Valacyclovir; Valganciclovir

PubMed: 30442095
DOI: 10.1186/s12879-018-3493-y

Authors: Neslihan Dilruba Koseoglu, Benjamin R Strauss, Pedram Hamrah...

PURPOSE

To describe 4 cases of presumably immunocompetent patients with herpes simplex virus (HSV) keratitis unresponsive (n = 3) or allergic (n = 1) to conventional antiviral therapy that improved with oral valganciclovir treatment.

METHODS

Retrospective case series of 4 patients with HSV keratitis treated with oral valganciclovir between March 2016 and June 2018.

RESULTS

We reviewed the records of 4 patients with recurrent epithelial HSV keratitis. Three patients were on antiviral prophylaxis because of a history of HSV keratitis. All patients were on oral acyclovir, valacyclovir, and/or famciclovir treatment with/without topical antiviral therapy for 4 to 6 months for prophylaxis and/or recurrent dendriform epithelial keratitis. While 3 patients had recurrent episodes during their active prophylaxis with oral antiviral therapies, one patient had a recurrence after she discontinued her oral prophylactic antiviral therapy due to recurrent self-reported allergic reactions. The patients presented with recurrent dendriform epithelial keratitis despite conventional antiviral therapy. We initiated oral valganciclovir 900 mg twice a day for 10 days as a treatment dose, followed by 900 mg daily for prophylaxis. The corneal epithelium subsequently healed within the first 2 weeks in all patients. The mean follow-up time for patients on valganciclovir prophylaxis was 8 months (range: 6-12 months), and none of the patients presented with any further recurrences.

CONCLUSIONS

In case of treatment-related side effects or failure with conventional antiviral therapies, oral valganciclovir may present an alternative for the treatment and prophylaxis of HSV keratitis.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antiviral Agents; Female; Humans; Keratitis, Herpetic; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Valganciclovir

PubMed: 30882539
DOI: 10.1097/ICO.0000000000001917

Authors: Karin Jorga, Bruno Reigner, Clarisse Chavanne...

Intravenous ganciclovir and oral valganciclovir are effective in the prevention and treatment of pediatric cytomegalovirus (CMV) infection but various dosing regimens are used in medical practice. Population pharmacokinetic (PopPK) model-based simulations were used to propose a new ganciclovir pediatric dosing algorithm for regulatory review and to evaluate the approved valganciclovir pediatric dosing algorithm against published dosing recommendations derived from quantitative approaches. Oral valganciclovir (mg = 7 × body surface area (BSA) × creatinine clearance according to the Schwarz formula (CrCLS) daily) and i.v. ganciclovir (mg = 3 × BSA × CrCLS daily) are effective in reaching ganciclovir target exposure for the prevention of CMV (area under the concentration-time curve (AUC) 40-60 μg ∙ hour/mL) in most pediatric patients across the full pediatric age range. In contrast, ganciclovir and valganciclovir dosing based on body weight, as commonly used in medical practice, leads to underexposure, particularly in younger pediatric patients. This example shows that model-based dosing algorithms built on clinical pharmacology and implemented using good modeling practice can prevent underexposure and reduce the risk of treatment failure in pediatric patients.

Topics: Adolescent; Algorithms; Antiviral Agents; Child; Child, Preschool; Computer Simulation; Cytomegalovirus Infections; Ganciclovir; Humans; Infant; Infant, Newborn; Models, Biological; Treatment Failure; Valganciclovir

PubMed: 30354026
DOI: 10.1002/psp4.12363