Dek: Prospective data suggest viral burden early in treatment may help identify solid organ transplant recipients at greater risk of recurrent cytomegalovirus DNAemia.
Higher cytomegalovirus viral loads early in treatment may help identify solid organ transplant recipients at increased risk for relapse after initial viral suppression, a prospective observational study found.
The study, published in Open Forum Infectious Diseases, included 62 solid organ transplant recipients with their first episode of clinically significant human cytomegalovirus DNAemia after transplantation. Fifteen patients, or 24%, experienced relapse within 6 months after initial viral suppression.
“Relatively simple information that clinicians already collect, such as early viral-load measurements, may eventually be combined with transplant type, serostatus, and measures of antiviral immunity to identify patients who require prolonged monitoring or additional preventive therapy, while potentially avoiding unnecessary treatment in lower-risk patients,” senior author Victor H. Ferreira, PhD, of the University Health Network in Toronto, said in an interview with IDSA Reporter.
Dr. Ferreira and colleagues prospectively enrolled patients from November 2013 through September 2018. Clinically significant DNAemia, defined as a viral load of at least 1,000 IU/mL, prompted antiviral treatment. Viral loads were measured at onset and weekly through week four. Relapse was defined as DNAemia of at least 1,000 IU/mL within 6 months after initial suppression.
Viral loads were consistently higher early in treatment among patients who later relapsed, with the difference reaching statistical significance at week two. However, the rate of viral decline did not differ significantly between groups. From onset through week four, the median viral decay slope was -0.052 log10 IU/mL per day among patients who relapsed vs -0.074 among those who did not.
Early viral load may be more useful for predicting relapse than the rate of viral decline, although larger studies are needed before it can guide clinical decisions, the researchers said.
Several clinical differences also emerged. Lung transplant recipients made up 73% of patients who relapsed vs 43% of those who did not. Donor-seropositive/recipient-seronegative status was present in 60% vs 40%, and end-organ HCMV disease in 40% vs 21%.
In an exploratory analysis of 33 patients, HCMV-specific CD4-positive and CD8-positive T-cell responses did not differ by relapse status. Patients who relapsed had more T cells expressing CTLA-4 at weeks one and four, although the authors cautioned that the findings were exploratory.
The small number of relapses limited the study’s ability to identify independent predictors, particularly in the immune analyses. Prevention strategies also varied, and low cell counts prevented detailed analysis of HCMV-specific T cells.
Larger, independent studies are needed to determine whether early viral loads can improve risk assessment and “support more individualized monitoring and antiviral management” for solid organ transplant recipients with HCMV, the authors concluded.
The Canadian Institutes of Health Research, Ajmera Transplant Centre and other institutional and scholarship support funded the work. Atul Humar, MD, reported grant support from Qiagen and speaker honoraria from Takeda, Eurofins and Kamada. The other authors reported no conflicts of interest.
Author Insight
Dr. Ferreira elaborated on the study results.
How might the finding that higher HCMV viral loads at week two were linked to relapse affect how clinicians monitor patients after starting antiviral treatment?
Dr. Ferreira: Our findings suggest that the viral load approximately two weeks after starting treatment may provide useful information about a patient’s subsequent risk of relapse. Patients who ultimately relapsed had higher viral loads early in treatment, with the difference reaching statistical significance at week two. Interestingly, the calculated rate of viral decline was not significantly different between groups, suggesting that the absolute amount of virus remaining at this early time point may be more informative than viral kinetics alone.
Clinically, this could mean paying particular attention to patients who continue to have relatively high-level DNAemia after the first couple of weeks of therapy. These patients might benefit from closer virologic follow-up during treatment and after suppression. However, our study was not designed to establish a specific viral load threshold or to demonstrate that changing treatment based on this measurement improves outcomes. Those questions would need to be addressed prospectively before this could become a formal treatment algorithm.
Which solid organ transplant recipients should clinicians consider at highest risk for HCMV relapse, and could these findings help guide decisions about secondary prophylaxis or closer monitoring?
Dr. Ferreira: Based on our cohort and the existing literature, I would be particularly concerned about patients with a high early viral burden, especially if they are lung transplant recipients or have a high-risk donor-positive/recipient-negative, or D+/R−, serostatus. In our study, 73% of patients who relapsed were lung transplant recipients compared with approximately 43% of those who did not relapse, and 60% of those who relapsed were D+/R− compared with about 40% in the non-relapse group. That said, we had only 15 relapse events, so we could not reliably determine which of these factors were independently predictive. In particular, the association with lung transplantation did not reach statistical significance in this cohort.
What do the T-cell findings add to our understanding of HCMV relapse, and are immune markers likely to become useful for predicting relapse in clinical practice?
Dr. Ferreira: The immune findings were exploratory but potentially informative. We did not find a clear difference in the magnitude of conventional HCMV-specific CD4 or CD8 T cell cytokine responses between patients who relapsed and those who did not. However, patients who subsequently relapsed had higher frequencies of CTLA-4-expressing CD4 and CD8 T cells at week one, with a similar pattern still evident at week four. That raises the possibility that the functional or activation state of the T cell compartment may matter in ways that are not captured simply by measuring whether HCMV-specific T cells are present. At this point, however, we cannot say whether CTLA-4 is itself a predictor of relapse or simply a marker of a broader immunologic state. I do think immune markers have the potential to become clinically useful, particularly if they can be combined with viral load and clinical risk factors.