High Incidence of Ganciclovir‐Resistant Cytomegalovirus Infection among Lung Transplant Recipients Receiving Preemptive Therapy

Limaye, Ajit P.; Raghu, Ganesh; Koelle, David M.; Ferrenberg, James; Huang, Meei‐Li; Boeckh, Michael

doi:10.1086/338143

Cited by 208 publications

(171 citation statements)

References 27 publications

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“…3 High-risk patients as HCMV seronegative recipients of a seropositive transplant (RϪ/D+) were not present, being found in the context of GCV resistance in lung transplant recipients. 13 All three patients were R+. Therefore, these assumed risk factors cannot be blamed for the development of resistance in the cases presented.…”

Section: Discussionmentioning

confidence: 88%

Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery

Eckle

Lang

Prix

et al. 2002

Bone Marrow Transplant

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Summary:As recently reported, children having T cell-depleted peripheral blood stem cell transplantation (PBSCT) might be at increased risk for the development of drug resistance. To investigate if delayed immune recovery was a potential risk factor, the recovery of the CD3 + , CD4 + , CD8 + and CD19 + cells was related retrospectively to genotypic detected resistance development in three pediatric patients with ganciclovir ( Keywords: HCMV; UL97; UL54; PBSCT; immune recovery; CD34 + blood stem cells Studies in AIDS patients made clear that ganciclovir (GCV) resistance develops in a slow but progressive manner. GCV-resistant human cytomegalovirus (HCMV) seems to infect immunocompromised patients who have either profound immunosuppression with very high viral loads or who have undergone long periods of therapy. 1 Until recently, there have been only scattered reports of GCV resistance in transplant recipients. As reported, in a study of 240 allograft recipients, subsets at special risk were HCMV-seronegative patients who received an organ from an HCMV-seropositive donor and those patients who required long periods of intense immunosuppression. On average, the patients in this report were treated with GCV for a mean of 190 days, which suggested that the duration of GCV exposure is also an important factor in the development of resistance. 2 In the BMT setting, there is even less knowledge about GCV resistance. After BMT in adults there exists to date only one report about a patient with phenotypic, as well as genotypic GCV resistance, 3 whereas a recent study using RFLP analysis limited to the detection of some frequent occurring UL97 mutations (codons: 460, 520, 594, 595) did not reveal any evidence for the emergence of GCV resistance in 10 out of 34 adults treated after PBSCT. 4 However, according to our experience the rapid emergence of GCV resistance in codons 591/603 should not be ignored. 5,6 Initially, Wolf et al 7 reported on the early emergence of GCV resistance in children with primary combined immunodeficiency (CID) after T cell-depleted BMT in four out of six cases. Recently, we also reported three children who developed GCV resistance after a short time of GCV therapy and we presented detailed longitudinal analyses of HCMV infection and resistance development after T cell depleted PBSCT. 6 General risk factors for resistance development, such as intense immunosuppression and prolonged exposure to GCV could not fully explain the rapid resistance development in our cases or in the patients with CID. 7

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Section: Discussionmentioning

confidence: 88%

Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery

Eckle

Lang

Prix

et al. 2002

Bone Marrow Transplant

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“…Coding point mutations associated with ACV resistance have also been described (6a, 8, 12, 23a, 23b, 25a, 29), but unlike in the example of human CMV and ganciclovir resistance (18), obvious clustering of such resistanceassociated point mutations in hot spots has not yet been recognized. We did detect two point mutations (L228I and R338Q) that map near known ACV resistance-associated sequence variants (D229H and C336Y, respectively) (12,27).…”

Section: Discussionmentioning

confidence: 99%

Use of Acyclovir for Suppression of Human Immunodeficiency Virus Infection Is Not Associated with Genotypic Evidence of Herpes Simplex Virus Type 2 Resistance to Acyclovir: Analysis of Specimens from Three Phase III Trials

et al. 2010

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Herpes simplex virus type 2 (HSV-2) is the most common cause of genital ulcer disease and is a cofactor forHIV-1 acquisition and transmission. We analyzed specimens from three separate phase III trials of acyclovir (ACV) for prevention of HIV-1 acquisition and transmission to determine if failure of ACV to interrupt HIV acquisition and transmission was associated with genotypic ACV resistance. Acyclovir (400 mg twice daily) or placebo was provided to HSV-2-infected persons at risk of HIV-1 infection in the Mwanza and HPTN 039 trials and to persons dually infected with HSV-2 and HIV-1 who had an HIV-negative partner in the Partners in Prevention study. We extracted HSV DNA from genital ulcer swabs or cervicovaginal lavage fluids from 68 samples obtained from 64 participants randomized to ACV and sequenced the HSV-2 UL23 gene encoding thymidine kinase. The UL23 sequences were compared with published and unpublished data. Variants were observed in 38/1,128 (3.4%) nucleotide positions in the UL23 open reading frame, with 58% of these encoding amino acid changes. No deletions, insertions, or mutations known to be associated with resistance were detected. Thirty-one of the variants (81.5%) are newly reported, 15 of which code for amino acid changes. Overall, UL23 is highly polymorphic compared to other loci in HSV-2, but no drug resistance mutations were detected that could explain the failure to reduce HIV incidence or to prevent HIV-1 transmission in these studies.Herpes simplex virus type 2 (HSV-2) is one of the most common sexually transmitted infections. The prevalence of infection is higher in many parts of the developing world, especially in some settings in sub-Saharan Africa, where up to 75 to 80% of women may be infected by the age of 35 years (26).The standard treatment for symptomatic primary and recurrent genital herpes and for suppression of genital herpes has primarily been acyclovir (ACV), a guanosine nucleoside analogue that inhibits replication of HSV. The inactive prodrug is phosphorylated to ACV triphosphate by HSV-encoded thymidine kinase. The active ACV triphosphate then inhibits viral DNA polymerase. Thymidine kinase is encoded by the HSV UL23 gene. The frequency of ACV resistance is increased in ACV-treated, immunosuppressed individuals and may reach 5% (25). However, ACV resistance has also occasionally been documented in immunocompetent persons in both the absence and presence of ACV therapy (8, 28a). Up to 95% of clinically significant ACV resistance is caused by mutations in the UL23 gene that limit thymidine kinase enzymatic activity and thus prevent initial phosphorylation of the drug (1a). These are typically insertions or deletions of a single nucleotide in a poly(G) or poly(C) tract, leading to a frameshifted open reading frame with a carboxy-terminal nonsense polypeptide and premature termination (1a). Point mutations that prevent or reduce recognition of ACV as a substrate occur at lower frequencies (1a). Compared to the much greater understanding of human cytomegalovirus (CMV) and g...

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“…More than 50% of SOT recipients show evidence of HCMV infection, with 10 to 50% of patients developing symptomatic disease, depending on the serostatus of the recipient (R) and donor (D) (221). Due to the absence of a host-derived HCMV-specific immune response, the highest risk for infection is the combination of a serologically negative patient receiving an organ from a serologically positive donor (R Ϫ /D ϩ ), with disease being more severe in this group of patients (155). While matching of seronegative recipients to seronegative donors would be ideal, the availability of organs means that this is impractical.…”

Section: Infection Of Immunocompromised Patientsmentioning

confidence: 99%

Immunobiology of Human Cytomegalovirus: from Bench to Bedside

2009

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SUMMARY Following primary infection, human cytomegalovirus (HCMV) establishes lifelong latency and periodically reactivates without causing symptoms in healthy individuals. In the absence of an adequate host-derived immune response, this fine balance of permitting viral reactivation without causing pathogenesis is disrupted, and HCMV can subsequently cause invasive disease and an array of damaging indirect immunological effects. Over the last decade, our knowledge of the immune response to HCMV infection in healthy virus carriers and diseased individuals has allowed us to translate these findings to develop better diagnostic tools and therapeutic strategies. The application of these emerging technologies in the clinical setting is likely to provide opportunities for better management of patients with HCMV-associated diseases.

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High Incidence of Ganciclovir‐Resistant Cytomegalovirus Infection among Lung Transplant Recipients Receiving Preemptive Therapy

Cited by 208 publications

References 27 publications

Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery

Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery

Use of Acyclovir for Suppression of Human Immunodeficiency Virus Infection Is Not Associated with Genotypic Evidence of Herpes Simplex Virus Type 2 Resistance to Acyclovir: Analysis of Specimens from Three Phase III Trials

Immunobiology of Human Cytomegalovirus: from Bench to Bedside

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