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Changing the paradigm of cytomegalovirus management among HSCT patients
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Cytomegalovirus infection occurs among approximately 40% of cytomegalovirus-seropositive patients within the first 100 days following hematopoietic stem cell transplant and is associated with high morbidity and high mortality among HSCT recipients.
It is one of the major causes of infectious complications following HSCT, contributing indirectly to complications such as graft-versus-host disease, graft failure, and bacterial and fungal infections. Evidence suggests that cytomegalovirus (CMV) infection is not only an enormous clinical burden, but a substantial economic burden as well.
Available treatments
For more than 2 decades, pre-emptive antiviral therapy with ganciclovir, valganciclovir, or foscarnet (Foscavir, Clinigen Healthcare) has been the standard approach for managing CMV infection.
Although this approach has reduced CMV end-organ disease and mortality, it also is associated with significant toxicities, including myelosuppression with ganciclovir or valganciclovir and nephrotoxicity with foscarnet. Pre-emptive therapy is costly, not only because of the costs associated with hospital readmissions, but also because of the costs associated with toxic antiviral drugs and management of their side effects. Prophylaxis against CMV among at-risk patients would, therefore, be a better approach. However, this approach has not been feasible because of the toxicity associated with available antiviral drugs.
In November, the FDA approved letermovir (Prevymis, Merck) — the first new antiviral drug in nearly 15 years to treat CMV — based on a phase 3 clinical trial showing that significantly fewer CMV-seropositive allogeneic HSCT recipients experienced the primary outcome of clinically significant CMV infection defined by the onset of CMV disease, initiation of pre-emptive therapy for CMV based on laboratory-confirmed viremia and disease risk, or early discontinuation for any reason through 24 weeks post-HSCT when treated with letermovir compared with placebo (37.5% vs. 60.6%). A reduction in the number of subjects who initiated pre-emptive therapy largely drove this primary outcome.
The side effect profile for letermovir was not substantially different from that for placebo. Higher incidence of dyspnea, myalgia, hyperkalemia, and alanine aminotransferase levels higher than five times the upper limit of normal occurred with letermovir, but most of these events were low grade.
Burden of CMV
Presentations at the 2018 BMT Tandem Meetings provided more insight into the clinical and economic burden of CMV infection and pre-emptive therapy.
A retrospective study from Melendez and colleagues found that at 100 days after HSCT, the cumulative incidence of post-HSCT CMV infection and disease was highest among CMV-seropositive recipients (~ 40%), those receiving grafts manipulated by ex-vivo T-cell depletion (50% with steroids), and those receiving grafts from cord blood (64%). Among CMV-seropositive recipients, the median duration of pre-emptive therapy appeared longest for those receiving grafts from cord blood (36 days) or from seronegative donors (28 days). CMV disease rates within 100 days after HSCT appeared similar across platforms and occurred primarily in the setting of GVHD.
Miguel and colleagues presented a study finding that recipients of haploidentical cord — or cord blood supported by half-matched bone marrow — and haploidentical HSCT had a higher risk for CMV infection (66% vs. 46% for others; P = .001) and earlier onset of CMV reactivation (25.2 days vs. 40.1 days) within 100 days after transplant. CMV reactivation, a major risk factor for CMV disease, appeared associated with a greater number of hospital readmissions and prolonged cumulative hospital length of stay during the first year after HSCT, and more frequent outpatient transplant clinic appointments within the first 100 days after HSCT.
A poster by Artau and colleagues showed that resistant and refractory CMV infections also are associated with a high rate of CMV disease and overall mortality, although there were no differences in outcomes between resistant and refractory infections.
Ghantoji and colleagues presented an analysis of 100 allogeneic HSCT recipients who were rehospitalized with CMV, in which CMV reactivation occurred at a median of 32 days after HSCT and 192 episodes of pre-emptive therapy occurred within the first year following transplantation. The mean length of stay among patients readmitted for pre-emptive therapy was 32 days for patients treated with ganciclovir and 41 days for those treated with foscarnet. The average direct cost for these patients was $126,038 (range, 7,866-641,841), and the mean cost of antiviral drugs per hospitalization ranged from $780 for valganciclovir to $2,410 for foscarnet. Total direct costs per encounter appeared significantly higher among patients who experienced foscarnet-associated nephrotoxicity than those without it ($284,006 vs. $112,195; P = .021).
Changing the paradigm
Other presentations hinted at possible ways to change the paradigm of CMV management.
Chen and colleagues presented a study that found that the average number of CMV reactivations was lower (0.36 to 0.42 vs. 1.03 to 1.24), and the time to the first reactivation longer (46 to 47.5 days vs. 40 days), among recipients receiving transplants from donors with anti-CMV immunity.
Brix and colleagues found that a lower level of post-HSCT anti-CMV immunity among HSCT recipients, as demonstrated by a lower number of CMV-specific CD3-positive, CD38-positive T cells, appeared associated with a higher risk for CMV antigenemia. These results suggest that monitoring for anti-CMV immunity among HSCT recipients might aid in assessing risk for CMV reactivation and, thus, in stratifying treatment of HSCT recipients.
Other presentations provided more insight into the potential impact of CMV prophylaxis.
Schelfhout and colleagues presented results from a cost-effectiveness model using letermovir phase 3 clinical trial data. If a cohort of 1,000 hypothetical patients are followed until death, letermovir prophylaxis would reduce the number of CMV infections requiring pre-emptive therapy (189 vs. 443) at 24 weeks after HSCT. It also can reduce CMV-associated mortality (102 cases vs. 159 cases), increase life-years by 481, increase quality-adjusted life years (QALYs) by 410, while increasing total costs from the time of transplant through 24 weeks after HSCT. These findings translate to an incremental cost-effectiveness ratio (ICER) of $29,110 per QALY gained and suggested that letermovir could be cost-effective at the commonly accepted ICER thresholds of $100,000 or $150,000 per QALY gained.
For more than 20 years, pre-emptive therapy has been the only option for managing CMV infection. However, this approach waits until after infection has occurred to start therapy, which is associated not only with serious side effects such as myelosuppression and nephrotoxicity, but also with high costs from hospital readmissions, treatment with toxic antiviral drugs, and management of side effects associated with those drugs. A cost-effectiveness model using clinical trial data would suggest letermovir prophylaxis results in better outcomes, and while the cost of prophylaxis would increase, there is the potential for some cost savings through the avoidance of readmissions and preemptive antiviral therapy.
Further, the potential contribution of anti-CMV immunity to CMV outcomes suggest that a shift in the paradigm of CMV management from one of pre-emptive therapy to one of CMV prophylaxis and monitoring for recipient anti-CMV immunity may have a profound impact on the CMV landscape.
References:
Marty FM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1706640.
Schelfhout J, et al. Abstract 2436. Presented at: IDWeek; Oct. 6-8, 2017; San Diego.
Teira P, et al. Blood. 2016;doi:10.1182/blood-2015-11-679639.
The following were presented at BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City:
Artau A, et al. Abstract 560.
Brix L, et al. Abstract 527.
Chen GL, et al. Abstract 572.
Ghantoji SS, et al. Abstract 542.
Schelfhout J, et al. Abstract 557.
Marty FM. The present and future of anti-CMV strategies: challenges, opportunities, and implications for the HCT clinician.
Melendez R, et al. Abstract 546.
Migues C de, et al. Abstract 565.
For more information:
Roy F. Chemaly, MD, MPH, FACP, FIDSA, is professor in the department of infectious diseases, infection control and employee health in the division of internal medicine at The University of Texas MD Anderson Cancer Center. He can be reached at rfchemaly@mdanderson.org.
Disclosure: Chemaly reports grants and personal fees from Chimerix, Merck and Oxford Immunotec; grants from Novartis and Shire; and personal fees from Astellas.