Title: Maribavir for treating refractory or resistant cytomegalovirus infection after transplant [ID3900]
Funder: Department of Health and Social Care

Abstract: Cytomegalovirus (CMV) is a common viral infection. Once a person is infected, CMV stays in the body for life and the person will have CMV antibodies (known as ‘seropositive’). The virus is carried by around 50% to 80% of the population.[1] For healthy people, CMV usually remains dormant and does not cause symptoms. However, for people undergoing transplants the virus can become active again (reactivation) because of a weakened immune system. Reactivation of CMV in this population can cause severe complications such as pneumonitis, colitis, retinitis and encephalitis.[2–4] CMV infections that are refractory or resistant to current treatments are a major cause of morbidity and mortality among people who have haematopoietic stem cell transplantation (HSCT) or solid organ transplant (SOT) such as heart, lung, kidney or liver transplants. [5] Additionally, people who do not carry CMV (known as ‘seronegative’) and receive an organ from seropositive donors are more likely to develop the disease and it can be more aggressive.[6]_x000D_ _x000D_ In 2019, 1,714 patients received HSCT in the UK.[7] It is reported that up to 50% of CMV seropositive recipients of HSCT experience CMV reactivation, regardless of the donor’s serostatus.[8] Any level of CMV is associated with increased risk of mortality in the first year after HSCT.[9] Over 4,700 SOTs were conducted in the UK between 2019 and 2020, most of which were kidney or liver transplants.[10] About 8% of renal, 29% of liver, 25% of heart and 39% of lung transplants can be expected to experience symptomatic CMV infection._x000D_ _x000D_ To reduce or prevent the effects of CMV infection or reactivation, people who have undergone transplants are given either universal prophylaxis or pre-emptive therapy. Prophylactic therapy is given to people who are at risk of developing CMV infection, while pre-emptive therapy is given when there is evidence of CMV replication in the blood. There are currently no treatments recommended by NICE for treating CMV infection that is refractory or resistant to other treatments. For CMV infection in people who have had a HSCT, current guidelines recommend antiviral therapy with ganciclovir, foscarnet or valganciclovir in first line setting according to individual characteristics such as ganciclovir tolerance, antiviral resistance or gastrointestinal function.[11] Foscarnet, cidofovir or ganciclovir and foscarnet combination can be used in second line, while cidofovir or ganciclovir and foscarnet combination are recommended in third line. Cytotoxic lymphocytes may be used as a last resort when all other treatments have failed. For people who have had a SOT, CMV infection is treated with ganciclovir (alone or in combination with hyperimmune globulins) or valganciclovir in first line setting, while foscarnet or cidofovir are used as second line treatment. [12] Foscarnet and cidofovir are both toxic to kidneys and may not be a treatment option for patients with significantly impaired kidney function. So, foscarnet may be reserved for third line setting because of kidney toxicity.[12]_x000D_ _x000D_ References_x000D_ 1 Medscape. Heuman DM, et al. (2019) Cytomegalovirus Colitis. Accessed February 2021._x000D_ 2 Park SC, Jeen YM, Jeen YT. Approach to cytomegalovirus infections in patients with ulcerative colitis. The Korean journal of internal medicine. 2017;32(3):383-92._x000D_ 3 Mombelli M, Manuel O. (2019) Cytomegalovirus infection. Accessed February 2021._x000D_ 4 Spector SA, Davis JL. (2002) Cytomegalovirus: Second Edition. Accessed February 2021._x000D_ 5 Papanicolaou GA, Silveira FP, Langston AA et al. (2019) Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study._x000D_ Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2019;68(8):1255-64._x000D_ 6 Azevedo LS, Pierrotti LC, Abdala E et al. (2015) Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo, Brazil). 2015;70(7):515-23._x000D_ 7 British Society of Blood and Marrow Transplantation and Cellular Therapies. (2019) BSBMTCT Registry: 2019 Annual Activity. 2019. Accessed February 2021._x000D_ 8 George B, Pati N, Gilroy N et al. (2010) Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transplant Infectious Disease. 2010;12(4):322-9._x000D_ 9 Green ML, Leisenring W, Xie H et al. (2016) Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. The Lancet Haematology. 2016;3(3):e119-e27._x000D_ 10 NHS Blood and Transplant. (2020) Organ Donation and Transplantation: Activity figures for the UK as at 9 April 2020. Accessed February 2021._x000D_ 11 Ljungman P, de la Camara R, Robin C et al. (2017) Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019 Aug;19(8):e260-e272._x000D_ 12 British Transplantation Society. (2015) The Prevention and Management of CMV Disease after Solid Organ Transplantation (Third Edition). Accessed February 2021.

Lay abstract: To appraise the clinical and cost effectiveness of maribavir within its marketing authorisation for treating refractory or resistant cytomegalovirus infection in people who have had a haematopoietic stem cell transplantation or solid organ transplant.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION