Despite advances in the prevention and treatment of CMV in allo-HSCT recipients, refractory CMV infection remains one of the major clinical challenges and severely affects patient outcomes [1].
Current status of treatment of refractory CMV infection
Currently, drug therapy for refractory CMV infection/disease is limited, and anti-CMV agents (ganciclovir/valganciclovir, foscarnet) that are not used in pre-emptive regimens are clinically available as monotherapy or in combination, but there is insufficient evidence to support the efficacy of combination therapy [2]. A 10-year retrospective analysis of a single center found that nearly one-third of patients treated with foscarnet (FOS) for ganciclovir (GCV)-resistant or refractory CMV infection failed viremia clearance and had a 31 percent viremia recurrence rate [3], and another retrospective study of the combination of GCV and FOS versus either monotherapy in patients with refractory CMV infection after allo-HSCT found GCV+There was no significant difference between FOS and monotherapy in the duration of CMV, the incidence of CMV, or the recurrence rate of CMV [4].
In addition, conventional anti-CMV agents are associated with serious adverse events, with the incidence of myelosuppression, neutropenia ranging from 30.0% to 39.8%, and nephrotoxicity in 11% in one systematic review with conventional anti-CMV agents, which can lead to treatment discontinuation (13.6%) [5], posing a dilemma in clinical management. Therefore, there is an urgent need for treatment regimens that have been proven to be effective and well tolerated.
Novel antiviral drugs
Recently, maribavir was approved for the treatment of cytomegalovirus (CMV) infection and/or disease following hematopoietic stem cell transplantation or solid organ transplantation, and in adult patients (with or without genotype resistance) who are refractory to one or more prior therapies (ganciclovir, valganciclovir, cidofovir, or foscarnet), let's look at the changes that maribavir brings about through pivotal studies.
Dose-finding studies[6]
The Phase II study is a multicenter, randomized, double-blind, dose-ranging exploratory study evaluating the efficacy and safety of different doses of maribavir (400, 800, and 1200 mg bid) for 24 weeks in patients with refractory CMV infection after HSCT and SOT.
Two-thirds of patients achieve negative CMV viremia within 6 weeks of treatment. No dose-related myelosuppressive effects of maribavir were observed, and 18 of the 19 patients who reported developing kidney injury had a history of kidney disease or elevated creatinine at baseline. The results support the safety and tolerability of maribavir for up to 24 weeks.
Figure 1. Efficacy data from a phase II dose-finding study
SOLSTICE STUDY[7]
The SOLSTICE study is a phase III, multicenter, randomized, open-label, active-controlled drug-controlled study of patients with refractory CMV infection/disease after HSCT and SOT who received maribavir or conventional antiviral (IAT: ganciclovir, valganciclovir, foscarnet sodium, or cidofovir) followed up to 20 weeks after 8 weeks. The primary endpoint was viral clearance at week 8, and the key secondary endpoints were viremia conversion and symptom control and maintenance to week 16 at week 8.
More patients in the maribavir group achieved negative CMV viremia at week 8 compared with conventional antivirals (55.7 versus 23.9 percent; P <0.001), and the proportion of patients who maintained viremia conversion and symptom control at 16 weeks after discontinuation of the drug was higher (18.7 versus 10.3 percent; P=0.01）。 The primary endpoint and key secondary endpoint results are shown in Figure 2.
Figure 2. Primary endpoint versus key secondary endpoint outcomes
Compared with conventional antiviral therapy, the median time to negative CMV viremia in the maribavir group was shortened by 5 days (22 versus 27 days, P=0.04). After week 8, among participants who met the primary endpoint, the rate of recurrence of infection was lower in the maribavir group (26.0%) than in the IAT (35.7%) group.
Figure 3. Exploratory endpoints
Compared with conventional antiviral therapy, patients in the maribavir group were at a lower risk of myelosuppression and nephrotoxicity. There were no cases of discontinuation due to treatment-related neutropenia or acute kidney injury in the maribavir group, compared with valganciclovir/ganciclovir discontinuation due to treatment-related neutropenia in 19.6% of patients in the usual care group (IAT group) and foscarnet discontinuation due to treatment-related acute kidney injury in 12.8% of patients.
Dysgeusia was the most common adverse reaction in the maribavir group (37.2%), most of which were mild and transient, and only 0.9% of patients discontinued the drug due to dysgeusia.
Figure 4. Bone marrow and kidney toxicity in the study
Long-term clinical outcomes[8]
To further explore the long-term clinical outcomes of maribavir, a multinational, observational, case-retrospective study followed 109 transplant recipients with post-transplant refractory CMV infection in the maribavir arm of SOLSTICE to 52 weeks (SOLSTICE trial: 20 weeks; medical record follow-up period: 32 weeks), with an overall mortality rate of 15.6% (17/109) , lower than the estimates reported in similar populations receiving conventional anti-CMV therapy (HSCT: 33.3-83%; SOT: 17-40%), and no new graft failed or required retransplantation during the case review period, suggesting that the benefit of maribavir over usual care was sustained until at least 52 weeks after initiation of maribavir therapy.
Utilization of medical resources[9]
CMV infection in transplant recipients is associated with higher hospitalization-related costs and increased length of hospital stay compared with uninfected patients, and multiple antiviral therapies can further increase costs. Further exploratory analysis of the healthcare resource utilization (HRU) of patients in the SOLSTICE trial was conducted to evaluate hospital admission data, including hospitalization and length of stay (LOS) by treatment group. The study found that patients treated with maribavir had a 34.8% reduction in hospitalization and a 53.8% reduction in length of stay (days/person/year) compared to IAT treatment.
Expert commentary
Refractory CMV infection after HSCT will increase the risk of a variety of adverse events, resulting in an increased risk of CMV end-organ disease and an increased mortality rate, which brings great challenges to the survival and quality of life of patients. At present, there are limited drug options for the treatment of refractory CMV, and the clinical treatment of refractory CMV is usually replaced with previously unused anti-CMV drugs or combination therapy, but even the combination of drugs does not significantly improve the clinical benefit, but may increase the treatment-limiting toxicity, and the treatment of refractory CMV still lacks reliable, effective and safe therapies, so there is an urgent need for innovative mechanisms, more effective, and treatment regimens with a lower risk of restrictive toxicities.
Maribavir, which is currently approved for the treatment of post-transplant refractory CMV infection, is a drug with an innovative mechanism. A number of studies have shown that maribavir has a good effect on refractory CMV infection after transplantation, and the incidence of bone marrow and renal adverse reactions is lower than that of conventional antiviral therapy, which can significantly reduce the medical burden. In addition, maribavir is an oral tablet, which can transfer the treatment of post-transplant refractory CMV to the outpatient setting, increasing the convenience of treatment. Current studies have shown the advantages of this drug in the treatment of post-transplant refractory CMV infection, and it is believed that maribavir will benefit more patients.
In conclusion, the management of refractory CMV infection after allo-HSCT requires a combination of factors to maximize the chances of treatment success while minimizing the risk of adverse effects in patients.
Prof. Feng Chen
- Department of Hematology, The First Affiliated Hospital of Soochow University: Chief Physician, Doctor of Medicine, Doctoral Supervisor
- Professional direction: hematopoietic stem cell transplantation, diagnosis and treatment of post-transplant complications
- Chinese Journal of Hematology: Corresponding Editorial Board
- Jiangsu Hematology Branch/Transplantation and Immunotherapy Group: Deputy Leader
- Jiangsu Provincial Research Hospital Association/ Transplantation and Immunotherapy Branch: Vice Chairman
bibliography
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2. Stem Cell Application Group, Hematology Branch, Chinese Medical Association. Chinese Expert Consensus on the Management of CMV Infection in Allogeneic Hematopoietic Stem Cell Transplant Patients (2022 Edition) [J] . Chin J Hematology, 2022, 43(8) :617-623.
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6. Papanicolaou, G.A., et al., Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study. Clin Infect Dis, 2019. 68(8): p. 1255-1264.
7. Avery, R.K., et al., Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial. Clin Infect Dis, 2022. 75(4): p. 690-701.
8. Bassel, M., et al., Retrospective chart review of transplant recipients with cytomegalovirus infection who received maribavir in the Phase 3 SOLSTICE trial: Data at 52 weeks post-maribavir treatment initiation. Antivir Ther, 2023. 28(5): p. 13596535231195431.
9. Hirji, I., et al., Healthcare resource utilization of maribavir versus investigator-assigned therapy in transplant recipients with cytomegalovirus infection refractory (with or without genotypic resistance) to prior treatment: Exploratory analysis of the Phase 3 SOLSTICE trial. Transpl Infect Dis, 2023. 25(3): p. e14064.
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