Incidence of UL97 Resistance Mutations in Infants with Congenital Cytomegalovirus Disease Receiving 6 Months of Oral Valganciclovir Therapy

Abstract Background A recently completed Phase 3 randomized, controlled, double-blind, multicenter study of infants with symptomatic congenital cytomegalovirus (CMV) disease receiving 6 months of oral valganciclovir (VGCV) therapy represents the largest such population in which to evaluate treatment-emergent antiviral resistance. The most common mechanism of CMV antiviral resistance occurs through mutations in the CMV UL97 gene that confer resistance to ganciclovir (GCV). Genotypic resistance analyses were performed on infants receiving 6 months of VGCV to assess the incidence of antiviral resistance due to UL97 sequence variants. Methods Resistance analyses were performed by conventional DNA sequencing of the UL97 gene at multiple time points. Following CMV DNA extraction from frozen whole blood specimens, the UL97 gene was amplified with a double nested polymerase chain reaction method and sequenced to identify polymorphisms and mutations that might confer GCV resistance. Results Forty-six infants with symptomatic CMV disease who received a 6-month course of VGCV underwent resistance analysis to identify UL97 sequence variants. In addition to a range of natural polymorphisms known to have no effect on antiviral susceptibility, 2 subjects developed UL97 mutations known to confer resistance to GCV (A594V and G598S detected in one subject; E596G detected in another), yielding an incidence of 4%. Each of these resistance mutations occurred in specimens collected after at least 4 months of antiviral therapy. As evaluated in the original Phase 3 trial, neither of these infants showed an improvement in hearing outcome. Conclusion The development of treatment-emergent UL97 resistance mutations was determined in a controlled study population of infants with congenital CMV disease receiving 6 months of VGCV. This targeted resistance analysis demonstrated an incidence approaching the total incidence of antiviral resistance for CMV disease in some immunocompromised populations, such as solid-organ transplant recipients. Further studies within this study population are warranted to elucidate the risk of emerging antiviral resistance and to assess clinical impact as well as the potential need for combination antiviral therapy. Disclosures All authors: No reported disclosures.

Download Full-text

Emergence of antiviral resistance during oral valganciclovir treatment of an infant with congenital cytomegalovirus (CMV) infection

Journal of Clinical Virology ◽

10.1016/j.jcv.2013.04.004 ◽

2013 ◽

Vol 57 (4) ◽

pp. 356-360 ◽

Cited By ~ 12

Author(s):

K. Yeon Choi ◽

B. Sharon ◽

H.H. Balfour ◽

K. Belani ◽

T.C. Pozos ◽

...

Keyword(s):

Antiviral Resistance ◽

Cmv Infection ◽

Congenital Cytomegalovirus ◽

Oral Valganciclovir

Download Full-text

Antiviral therapy for congenital cytomegalovirus infection in neonates and infants up to 12 months of age

Cochrane Database of Systematic Reviews ◽

10.1002/14651858.cd004340.pub2 ◽

2021 ◽

Vol 2021 (8) ◽

Author(s):

Cheryl A Jones ◽

Karen S Walker ◽

Hayley Smithers-Sheedy ◽

Amit Trivedi

Keyword(s):

Antiviral Therapy ◽

Cytomegalovirus Infection ◽

Congenital Cytomegalovirus Infection ◽

Congenital Cytomegalovirus ◽

Neonates And Infants

Download Full-text

Prevalence of UL97 gene mutations and polymorphisms in cytomegalovirus infection in the colon associated with or without ulcerative colitis

Scientific Reports ◽

10.1038/s41598-021-93168-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Satoshi Tamura ◽

Satoshi Osawa ◽

Natsuki Ishida ◽

Takahiro Miyazu ◽

Shinya Tani ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gene Mutations ◽

Pcr Amplification ◽

Kinase Domain ◽

Resistance Mutations ◽

Cmv Infection ◽

Nested Polymerase Chain Reaction ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Ul97 Gene

AbstractCytomegalovirus (CMV) reactivation in the colon is common in patients with severe ulcerative colitis (UC). Ganciclovir (GCV) resistance conferring CMV UL97 gene mutations have been reported in recent years. However, the prevalence of UL97 gene mutations in GCV-naive CMV infection in the colon remains unknown. We investigated the prevalence of CMV UL97 gene mutations in patients with colonic CMV infection associated with or without UC. Twenty-two GCV-naive patients with colonic CMV infection, 15 with UC and 7 with other diseases, were enrolled. Frozen biopsy samples or formalin-fixed paraffin-embedded samples were used for nested polymerase chain reaction (PCR) amplification of the UL97 gene. Sanger DNA sequencing was performed. In comparison with AD169 reference strain, natural polymorphisms were frequently detected in codons N68D (100%), I244V (100%), and D605E (86.4%). Seven polymorphisms were detected infrequently (< 10%) outside the kinase domain. However, no known GCV resistance mutations were found. There seemed to be no difference between the ratio of polymorphisms in patients with and without UC. In conclusions, we did not detect UL97 gene mutations associated with GCV resistance in GCV-naive patients with or without UC. Consistent with previous reports, D605E polymorphism may be used as a genetic marker for CMV in East Asian countries.

Download Full-text

High Risk Allogeneic Hematopoietic Cell Transplant (HCT) Patients with Any Level of Cytomegalovirus (CMV) Viremia Should Be Treated with Antiviral Therapy to Prevent Serious CMV Disease

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2012.11.463 ◽

2013 ◽

Vol 19 (2) ◽

pp. S312

Author(s):

Lena Winestone ◽

Rajni Agarwal ◽

Kenneth I. Weinberg ◽

Matthew Porteus ◽

Jennifer Reikes Willert ◽

...

Keyword(s):

High Risk ◽

Antiviral Therapy ◽

Hematopoietic Cell ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Allogeneic Hematopoietic Cell Transplant ◽

Cmv Disease

Download Full-text

Characterization of antiviral resistance mutations among the Eastern Indian Hepatitis B virus infected population

Virology Journal ◽

10.1186/1743-422x-10-56 ◽

2013 ◽

Vol 10 (1) ◽

pp. 56 ◽

Cited By ~ 10

Author(s):

Rajesh Panigrahi ◽

Avik Biswas ◽

Binay Krishna De ◽

Sekhar Chakrabarti ◽

Runu Chakravarty

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Antiviral Resistance ◽

Resistance Mutations ◽

Infected Population ◽

B Virus

Download Full-text

Multiple Influenza A (H3N2) Mutations Conferring Resistance to Neuraminidase Inhibitors in a Bone Marrow Transplant Recipient

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03667-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7188-7197 ◽

Cited By ~ 37

Author(s):

Alireza Eshaghi ◽

Sarah Shalhoub ◽

Paul Rosenfeld ◽

Aimin Li ◽

Rachel R. Higgins ◽

...

Keyword(s):

Influenza Virus ◽

Antiviral Therapy ◽

Influenza A ◽

Antiviral Treatment ◽

Marrow Transplant ◽

Viral Fitness ◽

H3n2 Virus ◽

Resistance Mutations ◽

Depth Analysis ◽

Resistant Strains

ABSTRACTImmunocompromised patients are predisposed to infections caused by influenza virus. Influenza virus may produce considerable morbidity, including protracted illness and prolonged viral shedding in these patients, thus prompting higher doses and prolonged courses of antiviral therapy. This approach may promote the emergence of resistant strains. Characterization of neuraminidase (NA) inhibitor (NAI)-resistant strains of influenza A virus is essential for documenting causes of resistance. In this study, using quantitative real-time PCR along with conventional Sanger sequencing, we identified an NAI-resistant strain of influenza A (H3N2) virus in an immunocompromised patient. In-depth analysis by deep gene sequencing revealed that various known markers of antiviral resistance, including transient R292K and Q136K substitutions and a sustained E119K (N2 numbering) substitution in the NA protein emerged during prolonged antiviral therapy. In addition, a combination of a 4-amino-acid deletion at residues 245 to 248 (Δ245-248) accompanied by the E119V substitution occurred, causing resistance to or reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir). Resistant variants within a pool of viral quasispecies arose during combined antiviral treatment. More research is needed to understand the interplay of drug resistance mutations, viral fitness, and transmission.

Download Full-text

Sequencing of Cytomegalovirus UL97 Gene for Genotypic Antiviral Resistance Testing

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.10.2775-2780.2001 ◽

2001 ◽

Vol 45 (10) ◽

pp. 2775-2780 ◽

Cited By ~ 62

Author(s):

Nell S. Lurain ◽

Adriana Weinberg ◽

Clyde S. Crumpacker ◽

Sunwen Chou

Keyword(s):

Drug Resistance ◽

Clinical Isolates ◽

Resistance Testing ◽

Virus Infectivity ◽

Resistance Mutations ◽

Sequence Identity ◽

Complete Sequences ◽

Immunosuppressed Patients ◽

Ul97 Gene ◽

Genotypic Assay

ABSTRACT The widespread use of ganciclovir (GCV) to treat cytomegalovirus (CMV) infections in immunosuppressed patients has led to the development of drug resistance. Phenotypic assays for CMV drug resistance are presently too time-consuming to be therapeutically useful. To support the development of genotypic assays for GCV resistance, the complete sequences of the UL97 phosphotransferase genes in 28 phenotypically GCV-sensitive CMV clinical isolates were determined. The gene was found to be highly conserved, with nucleotide sequence identity among strains ranging from 98.6 to 100% and amino acid sequence identity of >99%. Primers for a genotypic assay were designed to amplify codons 400 to 707, because all known UL97 mutations conferring drug resistance occur at three sites within this region. This part of the UL97 gene was amplified from over 50 clinical isolates, and two sequencing reactions for the coding strand were successfully used to identify GCV resistance mutations. This genotypic assay can be performed in 48 h using genomic DNA extracted from cell monolayers at very low levels of virus infectivity, thus rapidly providing therapeutically useful results.

Download Full-text

Efficacy, safety, and pharmacokinetics of oral valganciclovir in patients with congenital cytomegalovirus infection

Journal of Infection and Chemotherapy ◽

10.1016/j.jiac.2020.08.019 ◽

2020 ◽

Author(s):

Eisuke Suganuma ◽

Hideaki Sakata ◽

Nodoka Adachi ◽

Satoshi Asanuma ◽

Mihoko Furuichi ◽

...

Keyword(s):

Cytomegalovirus Infection ◽

Congenital Cytomegalovirus Infection ◽

Congenital Cytomegalovirus ◽

Oral Valganciclovir

Download Full-text

Prevalence of Invasive Cytomegalovirus Disease with Administration of Muromonab Cd-3 in Patients Undergoing Orthotopic Liver Transplantation

Annals of Pharmacotherapy ◽

10.1177/106002809202600501 ◽

1992 ◽

Vol 26 (5) ◽

pp. 617-620 ◽

Cited By ~ 15

Author(s):

Michael A. Hooks ◽

Carl A. Perlino ◽

J. Michael Henderson ◽

William J. Millikan ◽

Michael H. Kutner

Keyword(s):

Liver Transplant ◽

Data Extraction ◽

Transplant Recipients ◽

Early Administration ◽

Administration Time ◽

Study Population ◽

Cmv Disease ◽

Liver Transplant Recipients ◽

The Relationship ◽

Postoperative Administration

OBJECTIVE: To assess the association of cytomegalovirus (CMV) disease with the administration of muromonab CD-3 (OKT-3) in patients undergoing liver transplant; specifically, to assess the risk of OKT-3 use as an agent for rejection prophylaxis and as an agent for therapy of rejection. DESIGN: Retrospective review of medical records. STUDY POPULATION: 83 liver transplant recipients (43 men, 40 women) with a mean age of 41.5 years (range 16–62). DATA EXTRACTION: The medical record for each liver transplant recipient was reviewed and analyzed for the following variables: (1) preoperative recipient CMV serology, (2) donor CMV serology, (3) incidence of invasive CMV disease, (4) administration of OKT-3, (5) postoperative administration time of OKT-3, and (6) the relationship between the administration of OKT-3 and the prevalence of invasive CMV disease. RESULTS: OKT-3 was administered to 34 of 83 (40.9 percent) liver recipients, 7 of whom received OKT-3 as rejection prophylaxis; the remainder received OKT-3 as rejection rescue. All patients received OKT-3 5 mg iv for 14 days. Seventeen of the 34 patients receiving OKT-3 (50 percent) developed invasive CMV disease; 58.8 percent of the patients (20/34) receiving OKT-3 were given the agent within the first 14 postoperative days. Sixteen of these 20 patients (80 percent) developed invasive CMV disease. One of 14 patients (7.1 percent) who received OKT-3 after the first 14 postoperative days developed invasive CMV disease. Of those patients 94 percent (16/17) received OKT-3 in the first 14 postoperative days. This prevalence differed significantly from those receiving OKT-3 after the 14th postoperative day and those who did not receive OKT-3 at any time during their hospital course. CONCLUSIONS: The patients who received early administration of OKT-3 in our study had a greater risk of invasive CMV disease than did those who received OKT-3 later in the hospital course.

Download Full-text