Foscarnet therapy for ganciclovir-resistant cytomegalovirus retinitis after stem cell transplantation: effective monitoring of CMV infection by quantitative analysis of CMV mRNA

Abstract

Summary:We report three pediatric patients with ganciclovirresistant cytomegalovirus (CMV) retinitis who were successfully treated with foscarnet. The patients were recipients of hematopoietic stem cell transplantation (SCT) from HLA-mismatched donors. Because these patients had developed or experienced progressive CMV retinitis during ganciclovir therapy, they received foscarnet therapy at 60 mg/kg every 8 h. Their retinitis resolved promptly after initiating foscarnet therapy, suggesting foscarnet's effectiveness in treating ganciclovirresistant CMV infection. The amount of CMV mRNA was quantitatively measured using an NASBA technique, which amplified the ␤2.7 transcripts specific for CMV replication. This technique was useful for monitoring disease activity in a more rapid and sensitive manner than the PCR assay for CMV DNA. Bone Marrow Transplantation (2001) 27, 1141-1145. Keywords: cytomegalovirus; ganciclovir; foscarnet; resistance; hematopoietic stem cell transplantation; NASBA Cytomegalovirus (CMV) infections are a major cause of morbidity and mortality among immunocompromised patients, especially recipients of allogeneic hematopoietic stem cell transplantation (SCT) and patients with AIDS. The measurement of CD4 + T cell count is crucial in patients at high risk of CMV retinitis; CMV retinitis develops when CD4 + T cell counts have decreased to less than 100/ l. A combination of ganciclovir and intravenous immunoglobulin is effective in treating CMV diseases. However, the development of resistance to ganciclovir has been reported. [1][2][3][4] Foscarnet (trisodium phosphonoformate, PFA), a pyrophosphate analog, 5 has been used in patients with AIDS, and allogeneic SCT recipients. Because the viral inhibitory mechanism of foscarnet is distinct from that of ganciclovir, foscarnet might be useful in patients with ganciclovir-resistant CMV infection. 2,4,6 It usually takes 2 weeks for retinitis to heal on intravenous ganciclovir or foscarnet.We report the clinical and virologic results of foscarnet therapy in three recipients who underwent SCT and developed ganciclovir-resistant CMV retinitis. CMV activities were monitored with a nucleic acid sequence-based amplification (NASBA) technique, 7-9 which amplified the ␤2.7 transcripts specific for CMV replication. 10 Thus, detecting CMV mRNA indicates active viral replication, which is not proven when only viral DNA is detected. Patients and methods PatientsThis study included three patients with acute leukemia who received an allogeneic SCT between 1997 and 1999. The ages of patients 1, 2 and 3 were 10 years, 16 years and 10 months, respectively, and CMV retinitis developed 104, 103 and 42 days after SCT, respectively. The pre-transplant CMV serological status of donors and recipients was positive. Diagnosis of CMV retinitisOphthalmologic evaluation: Patients were evaluated by experienced ophthalmologists using indirect ophthalmoscopy at least every 4 weeks after SCT and whenever virologic examination proved positive. Criteria for the diagnosis of CMV retinitis...

Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

“…CMV-infected infants after HSCT were found to develop ganciclovir resistance associated with the UL97 protein kinase (Ohta et al, 2001;Gohring et al, 2009;Kim et al, 2012;Erice et al, 1989). However, in some cases, multiple UL97 and UL54 (DNA polymerase) mutations that conferred resistance to ganciclovir and foscarnet (Choi et al, 2014) or to all three currently available anti-CMV drugs (i.e.…”

Immune reconstitution complicated by CMV retinitis in a pediatric patient who underwent haploidentical CD34+-selected hematopoietic stem cell transplant for acute lymphoblastic leukemia

“…In this setting, some authors have shown that this complication occurs as early as day +10, day +42, day +64, and day +107 post-grafting, whilst the patient is severely lymphopenic and CMV is actively replicating [8][9][10]. Accordingly, it has been demonstrated that the adoptive transfer of donor-derived CMV-specific CD8+ or CD4+ cytotoxic T lymphocytes is protective against the development of CMV disease in recipients of an allogeneic HSCT and has the potential for clearing CMV viremia [19].…”

“…Most of the data on CMV retinitis have been derived from adult patients who received an unmanipulated HSCT using an unrelated or mismatched donor as stem cell source whilst cases after in vitro T-depletion or CD34+-positive selection have been less frequently reported, especially in pediatric patients [8][9][10].…”

Cytomegalovirus Retinitis in an Immunocompromised Infant:A Case Report and Review of the Literature

“…The use of oral valganciclovir as an alternative therapy is currently under evaluation since its bioavailability equals that of intravenous ganciclovir and it does not have the associated comorbidities of prolonged hospital stay and intravenous administration [6, 7]. Ohta et al [8] showed the efficacy and safety of foscarnet for treating pediatric patients with CMVR. Current treatment for CMV infection is intravenous ganciclovir for 3-6 weeks; however, there are still doubts regarding which infants should be treated and for how long.…”