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Frontiers in Microbiology 2022The appearance of drug-resistant mutations in UL54 DNA polymerase and UL97 kinase genes is problematic for the treatment of human cytomegalovirus (HCMV) diseases. During...
The appearance of drug-resistant mutations in UL54 DNA polymerase and UL97 kinase genes is problematic for the treatment of human cytomegalovirus (HCMV) diseases. During treatment of HCMV infection in a pediatric hematopoietic cell transplant recipient, H600L and T700A mutations and E576G mutation were independently found in the UL54 gene. Foscarnet (FOS; phosphonoformic acid) resistance by T700A mutation is reported. Here, we investigated the role of novel mutations in drug resistance by producing recombinant viruses and a model polymerase structure. The H600L mutant virus showed an increase in resistance to ganciclovir (GCV) by 11-fold and to FOS and cidofovir (CDV) by 5-fold, compared to the wild type, while the E756G mutant virus showed an increase in resistance to FOS by 9-fold and modestly to CDV by 2-fold. With the FOS-resistant T700A mutation, only H600L produced increased FOS resistance up to 37-fold, indicating an additive effect of these mutations on FOS resistance. To gain insight into drug resistance mechanisms, a model structure for UL54 polymerase was constructed using the yeast DNA polymerase as a template. In this model, HCMV DNA polymerase contains a long palm loop domain of which H600 and T700 are located on each end and T700 interacts with the FOS binding pocket. Our results demonstrate that H600L and E756G mutations in UL54 polymerase are novel drug-resistant mutations and that the acquisition of both H600L and T700A mutations in the DNA-binding loop confers increased resistance to FOS treatment, providing novel insights for the mechanism acquiring foscarnet resistance.
PubMed: 35185843
DOI: 10.3389/fmicb.2022.771978 -
Medicine Feb 2022Cytomegalovirus (CMV) disease is relatively uncommon in nontransplant hematological patients. Moreover, cutaneous manifestations of CMV diseases have scarcely been...
RATIONALE
Cytomegalovirus (CMV) disease is relatively uncommon in nontransplant hematological patients. Moreover, cutaneous manifestations of CMV diseases have scarcely been reported and are probably under-recognized.
PATIENT CONCERNS
We describe a patient with large B-cell lymphoma who developed a band-form, erythematous lesion over his left abdomen soon after the second course of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone chemotherapy.
DIAGNOSES
The lesion was initially mistaken for bacterial cellulitis or herpes zoster and was histologically confirmed as cutaneous CMV infection. Subsequent work-up also detected CMV viremia and the presence of CMV meningoencephalitis.
INTERVENTIONS
The patient was treated with ganciclovir plus CMV immune globulin followed by foscarnet.
OUTCOMES
Although the patient's cutaneous lesion resolved, his cognitive impairment did not recover, and he developed a fatal multi-organ failure 1 month later.
LESSONS
Cutaneous CMV disease can herald multisystem involvement and an unfavorable prognosis in immunocompromised hosts. It should be ruled out with biopsy in patients with hematological malignancy who have cutaneous lesions refractory to antibacterial therapy.
Topics: Antiviral Agents; Cytomegalovirus Infections; Fatal Outcome; Foscarnet; Ganciclovir; Hematologic Neoplasms; Humans; Immunocompromised Host; Male; Skin Diseases
PubMed: 35119018
DOI: 10.1097/MD.0000000000028721 -
Medicine Dec 2021Intraocular infection of Epstein-Barr virus (EBV) may cause severe visual loss. However, it is relatively rare, and there is no consensus on its treatment.
RATIONALE
Intraocular infection of Epstein-Barr virus (EBV) may cause severe visual loss. However, it is relatively rare, and there is no consensus on its treatment.
PATIENT CONCERNS
A 44-year-old woman complained of a right-eye floater and exhibited a unilateral exudative change along the retinal veins at the Department of Ophthalmology, St. Luke's International Hospital.
DIAGNOSIS
EBV retinitis was diagnosed based on EBV-positive (9.09 × 103 copies/μl) and cytomegalovirus-negative results in the aqueous humor.
INTERVENTIONS
Oral prescription of valaciclovir hydrochloride, and an intravitreal injection of foscarnet sodium hydrate was administered. However, the retinal infiltration progressed, and vitreous opacity with cellular infiltration appeared. Intravitreal methotrexate (MTX) injection effectively suppressed retinal and vitreous infiltration. However, she developed optic-nerve papillitis, and central retinal vein occlusion related to the severe swelling of the optic-nerve, and began steroid pulse therapy. Considering the increase in intraocular EBV levels to 6.4 × 104 copies/ml, we restarted intravitreal foscarnet injections replacing MTX. This in turn rapidly reduced the EBV levels to 3.27 × 104 copies/ml, followed by papillitis alleviation.
OUTCOMES
The intraocular MTX administration reduced the inflammatory vitreous and retinal infiltration, but not the EBV load, while foscarnet reduced the EBV load and papillitis, but not vitreous infiltration.
LESSONS
The retinal infiltration may have involved EBV infection to the retinal neurons but also EBV-free reactive inflammatory cells. EBV infection to the neurons may have been, at least partially, treated by intravitreal foscarnet treatment, and the reactive inflammatory cells by intravitreal MTX. Further observations are warranted to reach a consensus on treating intraocular EBV infection.
Topics: Adult; Epstein-Barr Virus Infections; Female; Foscarnet; Herpesvirus 4, Human; Humans; Methotrexate; Papilledema; Pulse Therapy, Drug; Retinitis; Steroids; Treatment Outcome
PubMed: 35049237
DOI: 10.1097/MD.0000000000028101 -
Anais Brasileiros de Dermatologia 2022
Topics: Acquired Immunodeficiency Syndrome; Acyclovir; Antiviral Agents; Foscarnet; Herpes Genitalis; Herpes Simplex; Humans; Imiquimod
PubMed: 35039209
DOI: 10.1016/j.abd.2020.10.019 -
Romanian Journal of Ophthalmology 2021To report a case of acute retinal necrosis (ARN) and to emphasize special aspects of the management. Factors that must be considered. We present the case of an...
To report a case of acute retinal necrosis (ARN) and to emphasize special aspects of the management. Factors that must be considered. We present the case of an 83-year-old woman examined for acute vision loss in her left eye (LE). Background: diabetes, pseudophakic in her LE; subluxated intraocular lens (IOL) and advanced pseudoexfoliative glaucoma in her right eye (RE). The visual acuity (VA) was hand movements in both eyes. Funduscopic examination revealed vitritis, temporal area of retinal necrosis with peripapillary choroiditis spots and macular haemorrhages in her LE and OCT showed a cystic macular edema. A positive polymerase chain reaction (PCR) test for Varicella Zoster Virus (VZV) in aqueous humor of her LE was found. She underwent intravenous Acyclovir 10 mg per kg every 8 hours. She received two doses of adjunctive intravitreal Foscarnet (2.4 mg/ 0.1 mL) in the first 3 days of treatment (2 days between doses). After 3 days of treatment, she started with intravenous prednisone 60 mg per day. The VA of her LE was 0,8 and the retinal necrosis activity was stationary. In fundoscopic examination, vitritis and retinal hemorrhages have disappeared. At that moment there were no foci of chorioretinitis or macular edema although retinal ischemia persisted at the inferior nasal level. The role of adjunctive intravitreal antiviral therapy in combination with systemic treatment revealed promising results. Corticosteroids can be used topically and orally to decrease the severe inflammatory response associated with ARN. Early treatment is crucial to optimize visual and anatomic outcomes.
Topics: Acyclovir; Aged, 80 and over; Eye Infections, Viral; Female; Foscarnet; Herpesvirus 3, Human; Humans; Retinal Necrosis Syndrome, Acute
PubMed: 35036649
DOI: 10.22336/rjo.2021.53 -
BMJ Case Reports Dec 2021The early engraftment phase of allogeneic haematopoietic stem cell transplantation can be associated with a number of oromucosal infective complications. While the...
The early engraftment phase of allogeneic haematopoietic stem cell transplantation can be associated with a number of oromucosal infective complications. While the routine use of prophylactic acyclovir has reduced the incidence of herpes simplex virus (HSV) reactivation, there is an increasing prevalence of acyclovir resistance within this cohort of patients. The authors present a case of acyclovir-resistant HSV reactivation in a 26-year-old woman 7 days post T-deplete sibling allograft on a background of combined cyclophosphamide and total body irradiation myeloablative conditioning, successfully treated with foscarnet and cidofovir therapy and discuss the differential diagnoses for early/late engraftment oral disease.
Topics: Acyclovir; Adult; Antiviral Agents; Female; Foscarnet; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans
PubMed: 34969809
DOI: 10.1136/bcr-2021-247109 -
Clinical Infectious Diseases : An... Sep 2022Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase.
METHODS
In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16.
RESULTS
352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs.
CONCLUSIONS
Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Drug Resistance, Viral; Foscarnet; Ganciclovir; Humans; Valganciclovir; Viremia
PubMed: 34864943
DOI: 10.1093/cid/ciab988 -
Clinical NephrologyFoscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced...
INTRODUCTION
Foscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits.
CASE PRESENTATION
A 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy.
CONCLUSION
Transplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.
Topics: Aged; Allografts; Antiviral Agents; Foscarnet; Ganciclovir; Humans; Kidney; Kidney Transplantation; Male; Nephritis, Interstitial
PubMed: 34643504
DOI: 10.5414/CNP96S23 -
Clinical Transplantation Nov 2021Letermovir (LTV) might be an alternative treatment to nephrotoxic foscarnet (FOS) in Ganciclovir (GCV) resistant cytomegalovirus (CMV) infection. However, its efficacy...
BACKGROUND
Letermovir (LTV) might be an alternative treatment to nephrotoxic foscarnet (FOS) in Ganciclovir (GCV) resistant cytomegalovirus (CMV) infection. However, its efficacy in controlling active CMV viremia is unclear, as it is only approved for CMV prophylaxis in hematopoietic stem-cell transplantation.
METHODS
This case series describes 14 kidney transplant recipients (KTR) with moderate-level GCV resistant CMV infection, treated by different step-down strategies after initial FOS therapy: (1) Observation without antiviral follow-up or switch to valganciclovir (VGCV) (pre-LTV era), and (2) Switch to LTV±VGCV (LTV era).
RESULTS
One patient died under FOS. Thirteen patients were followed under step-down regimens. All but two patients had ongoing CMV viremia when stopping FOS. In pre-LTV era, 5/9 (56%) experienced a CMV breakthrough > 10 000 IU/ml calling for another course of FOS, as compared to 1/4 (25%) in the LTV era. Addition of VGCV to LTV at low-level viral breakthrough, addressing a possible developing resistance against LTV, prevented viral surge in two patients. In the pre-LTV era, CMV-related death or graft loss occurred in three of nine (33%), compared to no death or graft loss in the LTV era.
CONCLUSION
A step-down strategy combining LTV+VGCV, might allow to safely stop FOS at ongoing low-level viremia.
Topics: Acetates; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Foscarnet; Ganciclovir; Humans; Kidney Transplantation; Quinazolines; Transplant Recipients; Valganciclovir
PubMed: 34181768
DOI: 10.1111/ctr.14401 -
BMJ Case Reports May 2021We present a 24-year-old man with a 2-year history of progressive right-sided monocular vision loss with no other symptoms. An MRI showed a meningioma compressing the...
We present a 24-year-old man with a 2-year history of progressive right-sided monocular vision loss with no other symptoms. An MRI showed a meningioma compressing the right optic nerve and the cavernous sinus. The tumour was partially resected. Eight days after discharge the patient was admitted with fever, a severe stabbing headache, insomnia, nausea and vomiting. A FilmArray panel and a cerebral biopsy were performed which were positive for herpes simplex virus 1 (HSV-1). An MRI of the brain showed asymmetric bilateral lesions in the frontobasal region with predominance of the right side. Acyclovir was started and continued until completing 21 days. A month after discharge, he started experiencing insomnia, trichotillomania, limb tremor, persistence of abulia, apathy and emotional lability. An HSV-1 encephalitis relapse was suspected, acyclovir and foscarnet were started. Due to the poor response to antiviral therapy CSF was tested, which was positive for anti-NMDA receptor encephalitis. A treatment course of intravenous immunoglobulin was started with a favourable outcome.
Topics: Acyclovir; Adult; Antiviral Agents; Encephalitis, Herpes Simplex; Foscarnet; Humans; Male; Neoplasm Recurrence, Local; Young Adult
PubMed: 34039543
DOI: 10.1136/bcr-2020-241136