Sorry Ganciclovir, You’re Just Not the One for Me
Important clinical considerations to know about resistant CMV infections.
Cytomegalovirus (CMV) viremia and CMV disease remain important causes of morbidity and nonrelapse mortality in immunocompromised patients, including recipients of allogeneic hematopoietic stem cell transplants (HSCTs) and solid organ transplants (SOTs) and those with acquired immunodeficiency syndrome. CMV is the most common clinically significant viral infection in HSCT and one of the most common opportunistic infections affecting the outcome of SOT.1,2
CMV viremia refers to the presence of viral DNA in the blood, whereas CMV disease refers to CMV-associated and biopsy-proven end organ damage. Positive cytopathologic changes (owl’s eye inclusions or viral inclusion bodies) are generally identified on immunofluorescent stain in CMV disease.1 Early detection of CMV disease via sensitive molecular assays, preemptive therapy with valganciclovir, and prophylaxis with letermovir through day 100 post transplant have reduced the incidence of disease in HSCT patients. Before the availability of effective therapy, CMV infection was the most serious infection for stem cell transplant recipients, with reactivation of CMV occurring in 15% to 30% of certain populations.3,4 Universal prophylaxis with valganciclovir or ganciclovir can reduce CMV disease in solid organ transplant recipients (SOTRs).5 Despite these improvements, refractory and/or resistant (R/R) CMV continues to contribute to nonrelapse mortality in HSCT recipients (HCTr).1
Refractory CMV infection is defined as an increase in viral load by more than 1log10 in blood or plasma after at least 2 weeks of an appropriately dosed CMV antiviral (ganciclovir and valganciclovir).1 Resistant CMV infection is defined as the presence on genotypic analysis of known viral genetic mutations that decrease susceptibility to CMV antivirals.1,5 In addition, R/R CMV disease also includes persistent clinical signs and symptoms of CMV disease to affected organ(s). One example is colitis, which is the most common presentation of CMV disease after HSCT.1 R/R CMV is also associated with allograft loss or rejection and increased morbidity and mortality in SOTRs.1,5
RISK FACTORS
Risk factors for CMV infection/disease in SOTRs include intense immunosuppression (via lymphocyte-depleting antibodies like antithymocyte thymoglobulin and alemtuzumab), high-dose corticosteroids, acute rejection, advanced age of donor, concurrent infections, and genetic polymorphisms.6 The greatest risk factor is serological donor/recipient mismatch: D+/R- for SOTRs and D-/R+ for HCTr. D+/R+ constitute intermediate risk and D-/R- low risk.1,6 Additional risk factors for HCTr include stem cell source, with umbilical cord blood transplant posing a higher risk than an alternative source. Recipients with active graft-vs-host disease (GVHD) also have a higher risk of CMV disease.7
Risk factors for R/R CMV include haploidentical and T cell—depleted HSCT, previous or prolonged antiviral drug exposure (>5 months), ongoing active viral replication in the setting of CMV nonimmunity, subtherapeutic antivirals, variation in CMV antiviral drug clearance, inadequate antiviral drug absorption and bioavailability, high levels of DNAemia, lymphopenia, GVHD, and a CMV seronegative donor.1,5,8 Protective factors include less intense immunosuppression, T cell–replete HSCT, use of mTOR inhibitors such as sirolimus and everolimus, and sometimes universal prophylaxis instead of preemptive therapy (preemptive therapy has a higher rate of ganciclovir resistance).1,5
WHEN TO SUSPECT CMV RESISTANCE
The lack of clinical improvement and/or a persistently elevated viral load, a rising viral load while on appropriate therapy, or a rebound in viral load after initial response defines refractory CMV infection.8 In these cases, drug resistance should be evaluated by genotypic analysis looking for CMV DNA. It is important to note that an increase or inappropriate reduction of viral load during the first 2 weeks of therapy is not a reliable indicator of drug resistance.5
CONFIRMING RESISTANCE AND MECHANISMS OF RESISTANCE
If CMV resistance is suspected, detecting associated mutations via CMV DNA genotyping is recommended for confirmation. These mutations include the CMV UL97 kinase gene that encodes varying degrees of resistance to ganciclovir. UL97 kinase, which is similar to herpes simplex virus thymidine kinase, is responsible for phosphorylation of nucleosides to triphosphate forms to be incorporated by UL54 DNA polymerase into growing strands of CMV DNA. This mutation decreases the phosphorylation of ganciclovir while preserving UL97 kinase function.9
Mutations in the UL54 DNA polymerase gene can cause varying degrees of cross-resistance between ganciclovir, cidofovir, and/ foscarnet.5,9 Mutations affecting the exonuclease domain encode for ganciclovir and cidofovir resistance, while foscarnet resistance mutations encountered in clinical practice tend to involve finger polymerase structure domains, which in turn may confer a low-grade ganciclovir and cidofovir cross-resistance. These mutations differ from those preferentially selected under ganciclovir, in which high-grade foscarnet resistance is rare.9
TREATMENT
Treatment of R/R CMV depends on the specific mutations associated with first-line ganciclovir. If the mutations present in UL97 (M460I, C592G, L595W), which encodes low-level resistance to ganciclovir, a higher dose of ganciclovir (7.5-10.0 mg/ kg every 12 hours instead of 5.0 mg/kg every 12 hours) should be considered. However, this approach is associated with higher incidence of bone marrow suppression and neutropenia. Granulocyte colony-stimulating factor, such as filgrastim, should be considered to mitigate myelosuppression.
When the mutations encode high-level resistance to ganciclovir, first-line treatment is foscarnet, and second-line therapy is cidofovir, both of which are associated with significant renal toxicity.1,5 Foscarnet and cidofovir do not require phosphorylation by UL97 to be incorporated into the growing strand of DNA, so these drugs are not affected by UL97 mutations.
Maribavir, a UL97 inhibitor with a mechanism of action different from ganciclovir’s, was approved by the FDA in December 2021.10 It inhibits CMV DNA replication, encapsidation, and nuclear egress of viral capsids via inhibition of UL97 protein kinase and its natural substrates. Maribavir should be considered in patients with R/R CMV infection who have a UL97 mutation, myelosuppression, and/or nephrotoxicity. In the phase 3 SOLSTICE trial (NCT02931539) evaluating viral clearance of CMV DNAemia with or without symptom control, maribavir was superior to investigator-assigned therapy (valganciclovir, ganciclovir, cidofovir, or foscarnet), including for posttherapy maintenance. Maribavir was associated with significantly less toxicity, including neutropenia and nephrotoxicity11; although it maintains activity against CMV that is resistant to ganciclovir, foscarnet, and cidofovir. Maribavir is not active in CNS and ocular infections because it does not cross the blood-brain barrier.10
Maribavir should also be considered for the treatment of R/R CMV infection in patients with UL54 mutations because the mutation usually confers cross-resistance to cidofovir and foscarnet. If maribavir is not available, foscarnet with or without adjunctive leflunomide or artesunate can be considered for UL54 mutations that encode resistance to cidofovir and ganciclovir. Cidofovir can be considered when dual resistance to ganciclovir and foscarnet is detected without cidofovir resistance.1 If resistance to all 3 drugs is detected, foscarnet in combination with high-dose ganciclovir (7.5-10.0mg/kg every 12 hours) should be considered. Another adjunctive option is CMV-specific T-cell therapy.1,5
Letermovir inhibits the UL56 viral terminase complex, which prevents cleavage of long DNA concatemers into individual viral subunits resulting in noninfectious DNA particles. In 2017, letermovir was approved by the FDA and indicated for prophylaxis of CMV infection and disease in adult CMV seropositive recipients of HSCT. At that time, it was the first new medicine for CMV infection approved in the United States in 15 years. Although effective at reducing incidence of R/R CMV infection/disease, drug-resistant CMV has emerged during use of letermovir for prophylaxis and/or treatment, suggesting it may have a low barrier to resistance.8,12
In a retrospective study, letermovir use was shown to prevent R/R CMV in HSCT and decrease nonrelapse mortality at 48 weeks.8 The rate of CMV breakthrough with letermovir as primary prophylaxis in SOTR was not statistically significant compared with the rate with valganciclovir, but it was noted that letermovir increased the whole blood levels of tacrolimus and of calcineurin inhibitors.13 Letermovir can be an option to prevent R/R CMV disease in SOTRs and HSCTr.13 The role of letermovir in treatment of established CMV infection or disease remains unclear. Patients treated with letermovir with a viral load of less than 1000 IU/mL had good virologic outcomes. Outcomes were mixed when letermovir was initiated at higher viral loads.14 In one case series, the emergence of a letermovir-resistant CMV UL56 mutant was detected during treatment of ganciclovir-resistant CMV infection.15,16
CONCLUSION
CMV viremia and CMV disease remain important causes of morbidity and mortality in immunocompromised patients, including HCTr and SOTRs. CMV resistance should be suspected when appropriate therapy leads to no clinical improvement or to elevated/ increasing viral load and when initial response is followed by viral rebound. If CMV resistance is suspected, CMV DNA genotyping is recommended. Mutations in UL54 DNA polymerase gene can cause varying degrees of cross-resistance between antiviral agents and should be considered when selecting therapy. Caution should be used with letermovir in the treatment of R/R CMV owing to the emergence of resistant mutations. Maribavir remains an important option in this setting due to its better toxicity profile than that of other currently available therapies.
References
1. Yong MK, Shigle TL, Kim YJ, Carpenter PA, Chemaly RF, Papanicolaou GA. American Society for Transplantation and Cellular Therapy Series: #4 - Cytomegalovirus treatment and management of resistant or refractory infections after hematopoietic cell transplantation. Transplant Cell Ther. 2021;27(12):957-967. doi:10.1016/j.jtct.2021.09.010
2. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 2019;33(9):e13512. doi:10.1111/ctr.13512
3. Keating M, Coutré S, Rai K, et al. Management guidelines for use of alemtuzumab in B-cell chronic lymphocytic leukemia. Clin Lymphoma. 2004;4(4):220-227. doi:10.3816/clm.2004.n.002
4. Winston, D.J., W.G. Ho, and R.E. Champlin, Cytomegalovirus infections after allogeneic bone marrow transplantation. Rev Infect Dis, 1990. 12 Suppl 7: p. S776-92.
5. Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018;102(6):900-931. doi:10.1097/TP.0000000000002191
6. Azevedo LS, Pierrotti LC, Abdala E, et al. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015;70(7):515-523. doi:10.6061/clinics/2015(07)09
7. Sassine J, Khawaja F, Shigle TL, et al. Refractory and Resistant Cytomegalovirus After Hematopoietic Cell Transplant in the Letermovir Primary Prophylaxis Era. Clin Infect Dis. 2021;73(8):1346-1354. doi:10.1093/cid/ciab298
8. Chemaly RF, Chou S, Einsele H, et al. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019;68(8):1420-1426. doi:10.1093/cid/ciy696
9. Chou, S., Approach to drug-resistant cytomegalovirus in transplant recipients. Curr Opin Infect Dis, 2015.28(4):p.293-9.
10. Gandhi, R.G. and C.N. Kotton, Evaluating the Safety of Maribavir for the Treatment of Cytomegalovirus. Ther Clin Risk Manag, 2022. 18: p. 223-232.
11. Avery RK, Alain S, Alexander BD, et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial [published correction appears in Clin Infect Dis. 2023 Feb 8;76(3):560]. Clin Infect Dis. 2022;75(4):690-701. doi:10.1093/cid/ciab988
12. El Helou, G. and R.R. Razonable, Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review. Infect Drug Resist, 2019. 12: p. 1481-1491.
13. Winstead RJ, Kumar D, Brown A, et al. Letermovir prophylaxis in solid organ transplant-Assessing CMV breakthrough and tacrolimus drug interaction. Transpl Infect Dis. 2021;23(4):e13570. doi:10.1111/tid.13570
14. Imlay, H.N. and D.R. Kaul, Letermovir and Maribavir for the Treatment and Prevention of Cytomegalovirus Infection in Solid Organ and Stem Cell Transplant Recipients. Clin Infect Dis, 2021. 73(1): p. 156-160.
15. Hofmann, E., et al., Emergence of letermovir resistance in solid organ transplant recipients with ganciclovir resistant cytomegalovirus infection: A case series and review of the literature. Transpl Infect Dis, 2021. 23(3): p. e13515.
16. Paolucci S, Campanini G, Cassaniti I, et al. Emergence of Letermovir-resistant HCMV UL56 mutant during rescue treatment in a liver transplant recipient with ganciclovir-resistant infection HCMV: a case report. BMC Infect Dis. 2021;21(1):994. Published 2021 Sep 23. doi:10.1186/s12879-021-06694-4
