Reactions Weekly | 2021
Antivirals/immunosuppressants
Abstract
Various toxicities and lack of efficacy: 2 case reports In a case report, 2 patients including a 64-year-old man and a 49-year-old patient [not all sexes stated] were described, who developed cytomegalovirus (CMV) infection, CMV viral syndrome, CMV viraemia or colitis during immunosuppression treatment with prednisone, tacrolimus, basiliximab, mycophenolate mofetil, azathioprine, ciclosporin or methylprednisolone. Additionally, the patients exhibited lack of efficacy with valganciclovir or ganciclovir for the prevention of CMV infection, exhibited lack of efficacy while receiving treatment with prednisone, tacrolimus, basiliximab, mycophenolate mofetil, ciclosporin or azathioprine for the prevention of renal transplant rejection and also exhibited lack of efficacy following an off-label treatment with letermovir as secondary prophylaxis to prevent CMV infection [not all dosages, routes and outcomes stated]. Case 1: A 64-year-old man developed CMV infection and CMV viral syndrome during immunosuppression treatment with prednisone, tacrolimus, basiliximab and mycophenolate mofetil, CMV viraemia during immunosuppression treatment with methylprednisolone, prednisone, mycophenolate mofetil and ciclosporin and colitis during immunosuppression treatment with mycophenolate mofetil. Additionally, he exhibited lack of efficacy with valganciclovir for the prevention of CMV infection, exhibited lack of efficacy while receiving treatment with prednisone, tacrolimus, basiliximab, mycophenolate mofetil and ciclosporin for the prevention of renal transplant rejection and also exhibited lack of efficacy following an off-label treatment with letermovir as secondary prophylaxis to prevent CMV infection. The man, who had chronic urinary tract obstruction, underwent kidney transplantation. He received immunosuppression treatment with prednisone, tacrolimus and mycophenolate mofetil. Additionally, basiliximab induction was used. At the time of transplantation, he received prophylactic treatment with valganciclovir for the prevention of CMV infection. Three months later, he developed primary breakthrough CMV infection despite treatment with valganciclovir. Thus, lack of efficacy with valganciclovir was considered. The CMV infection was attributed to the prednisone, tacrolimus, basiliximab and mycophenolate mofetil therapy. At that time, no CMV mutations associated with drug resistance in UL97, UL54, UL56, UL89 and UL51 were noted and valganciclovir was continued in increased therapeutic dosage. Despite an initial viral response and the presence of CMV-specific T-cells, the CMV viral load increased during valganciclovir treatment, and he developed persistent diarrhoea. Six months after the transplantation, CMV resistance was noted with various mutations. Colonoscopy showed histopathological changes compatible with mycophenolate mofetil-related colitis; however, CMV colitis could not be confirmed. Due to mycophenolate mofetil-related colitis and to improve the immune function, his therapy with mycophenolate mofetil was stopped. At this time, he refused foscarnet treatment. Therefore, valganciclovir was continued. Nine months after the transplantation, steadily increasing CMV viral load showed CMV resistance. After developing CMV viral syndrome secondary to the prednisone, tacrolimus, basiliximab and mycophenolate mofetil therapy, he agreed to receive treatment with foscarnet. Additionally, his tacrolimus treatment was switched to ciclosporin [cyclosporine A]. After foscarnet therapy, CMV viral load decreased to undetectable levels. After 8 weeks of treatment and one week of undetectable CMV viraemia, the foscarnet therapy was stopped. Subsequently, he received an off-label treatment with letermovir 240mg once daily as secondary prophylaxis to prevent CMV infection. During the follow-up, low level viraemia was intermittently observed. Due to progressive deterioration of the renal function, renal biopsy was performed, which revealed cellular allograft rejection (kidney transplant rejection). Therefore, lack of efficacy with prednisone, tacrolimus, basiliximab, mycophenolate mofetil and ciclosporin was considered. Rejection was then treated with a short course of methylprednisolone 500 mg once daily for 3 days followed by tapered dose of prednisone. Subsequently, his therapy with mycophenolate mofetil was restarted and the dose of ciclosporin was increased. Shortly after the immunosuppression therapy with methylprednisolone, prednisone, mycophenolate mofetil and ciclosporin, he developed severe fatigue, indicating CMV viraemia. Therefore, CMV viraemia was attributed to the methylprednisolone, prednisone, mycophenolate mofetil and ciclosporin therapy. Additionally, lack of efficacy with letermovir therapy was also considered due to the development of CMV viraemia. Therefore, letermovir therapy was stopped, and his foscarnet therapy was restarted. Thereafter, his immunosuppressive therapy was switched to everolimus, and the dose of ciclosporin was reduced. Additionally, CMV immunoglobulins were administered. After the CMV viral load dropped below the limit of detection for 2 weeks, his therapy with foscarnet was stopped. Subsequently, the CMV-specific cell mediated immunity increased, and he was able to immunologically control CMV viral load on a low level. Case 2: A 49-year-old patient developed CMV infection during immunosuppression treatment with azathioprine, prednisone and ciclosporin. Additionally, the patient exhibited lack of efficacy with ganciclovir and valganciclovir for the prevention of CMV infection and exhibited lack of efficacy while receiving treatment with azathioprine, prednisone and ciclosporin for the prevention of renal transplant rejection and also exhibited lack of efficacy following an off-label treatment with letermovir as secondary prophylaxis to prevent CMV infection. The patient, who underwent renal transplantation 18 years previously, was admitted to the outpatient service due to recurrent CMV infection. The patient had been receiving maintenance immunosuppressive regimen including azathioprine, prednisone and ciclosporin [cyclosporine A]. The CMV infection was attributed to the azathioprine, prednisone and ciclosporin therapy. The patient also reported that the patient had multiple rejection episodes (kidney transplant rejection) on follow-up visits. Therefore, lack of efficacy with azathioprine, prednisone and ciclosporin was considered. At the time of renal transplantation, the patient received ganciclovir prophylaxis followed by several courses of IV ganciclovir and long-term treatment with oral valganciclovir for the prevention of CMV infection. Despite valganciclovir and ganciclovir treatment, asymptomatic CMV replication was detectable. Thus, lack of efficacy with valganciclovir and ganciclovir was considered. Resistance testing showed a CMV UL97 mutation. Since the mutation does not cause ganciclovir high level resistance, IV high-dose ganciclovir 2.5 mg/kg twice daily was administered and azathioprine therapy was stopped. Despite these measures, no adequate decrease in CMV viral load was noted and the infection progressed to CMV tissue invasive disease with retinal and GI involvement. Therefore, the patient was treated with foscarnet. After 6 weeks, CMV viral load decreased to undetectable levels, retinal lesions improved and diarrhoea stopped. Therefore, foscarnet therapy was stopped. The patient subsequently received an off-label treatment with letermovir 240mg once daily as secondary prophylaxis to prevent CMV infection. Additionally, CMV immunoglobulins were administered. Three weeks after the initiation of letermovir therpy, the patient was diagnosed with an Epstein-Barr virus (EBV) positive GI monomorphic post-transplant lymphoproliferative disorder (PTLD). Therefore, the patient was treated with CHOP-21 chemotherapy including cyclophosphamide, doxorubicin, prednisolone and vincristine. Additionally, drug-drug interaction between ciclosporin and letermovir was considered. After the diagnosis of EBV-associated PTLD, ciclosporin was administered in reduced dosage for 2 weeks and then stopped completely without dose adjustment. Thereafter, immunosuppression treatment was continued with prednisone monotherapy. After 3 weeks of insufficient letermovir dosing, CMV viral load increased without clinical symptoms. The previous inadequate low dosage of letermovir triggered CMV resistance testing and showed combined CMV UL97 (C607F) and a UL54 mutations. Therefore, letermovir was stopped, the patient’s therapy with foscarnet was restarted. After achieving complete viral suppression with foscarnet therapy, foscarnet therapy was stopped and secondary CMV prophylaxis with 1