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Abstract

Background/objective:

Prevention of cytomegalovirus (CMV) infection is an important component of post kidney transplant care. We aimed to evaluate the impact of two different CMV prophylaxis protocols on the epidemiology and outcomes of CMV infections at our centre.

Methods:

This is a single-centre retrospective before/after observational study. Kidney transplant recipients who received Protocol 1, a valacyclovir- or valganciclovir-based regimen prescribed for one to three months based on the CMV risk status between 2004 and 2008, were compared to those who received Protocol 2, a valganciclovir-based regimen prescribed for three months and six months for those at moderate and high risk, respectively, between 2010 and 2014. The impact of different prophylaxis regimens on the incidence of CMV infections, disease, recurrent infections and onset of CMV infection at 24 months were reviewed.

Results:

There were 192 patients included; 106 patients received Protocol 1, 86 received Protocol 2. At 24 months, the incidence of CMV infection was 53.8% and 55.8% in Protocols 1 and 2, respectively (p=0.884). The incidence rates of CMV disease and recurrent CMV infections were higher in Protocol 1, but this was not statistically significant. The median time to first CMV infection was significantly shorter in patients who received Protocol 1: 132 days (interquartile range (IQR) 125–139 days) versus 185 days (IQR 178–192 days), p=0.001. Both prophylaxis protocols were well tolerated.

Conclusion:

The incidence of CMV infection was similar in both protocols. Where valganciclovir is not available, valacyclovir may be considered over no prophylaxis. Post-prophylaxis CMV infections are not uncommon, and vigilance for it should be advocated.

Keywords

Prophylaxis cytomegalovirus renal transplant valganciclovir valacyclovir

Introduction

Cytomegalovirus (CMV) is a medically important pathogen in kidney transplantation, and it is associated with graft rejection, graft dysfunction, graft loss and mortality.^1–4 Therefore, CMV prevention is an important component of post-transplant care.

CMV prevention strategies vary within and between institutions. Either universal prophylaxis or pre-emptive therapy is practiced.⁵ For universal prophylaxis, antiviral agents such as oral ganciclovir, valganciclovir and valacyclovir have been used.⁶ Oral ganciclovir is not recommended due to its lower bioavailability which may predispose to emergence of resistance.⁷ Valganciclovir, a prodrug of ganciclovir, has good bioavailability and is the most potent and preferred prophylaxis agent in most transplant centres. However, it is expensive, and prophylaxis duration may sometimes be truncated due to valganciclovir-induced leucopaenia. High-dose valacyclovir is a cost-effective alternative for CMV prophylaxis but can be associated with neurotoxicity.^8,9 Selection of CMV prophylaxis strategy and agents is also influenced by local prescribing patterns and available resources.

At Singapore General Hospital (SGH), universal prophylaxis is practised. There was a change in CMV prophylaxis recommended for kidney transplant, and this was more widely implemented after 2009 (see Table 1). Before 2009, patients at moderate risk for CMV (R+ recipients) received one month of CMV prophylaxis with valacyclovir, while those at high risk (R+ recipients who received thymoglobulin, D+/R– recipients) received three to six months of valacyclovir- or valganciclovir-based prophylaxis. After 2009, the protocol was intensified. Valganciclovir was exclusively used for prophylaxis, and prophylaxis duration was extended to three months for those at moderate risk and to six months for those at high risk. The change in prophylaxis regimen was driven by data which showed that the rates of CMV disease and viraemia were reduced when prophylaxis duration was prolonged in high-risk transplant recipients.¹⁰ This study aimed to evaluate the impact of intensifying CMV prophylaxis on our local renal transplant population.

Table 1.

CMV prophylaxis strategies practiced at SGH during the different study periods.

CMV serostatus	Protocol 1 (2004–2008)	Protocol 2 (2010–2014)
Low risk
D–R–	None	Valganciclovir ×1 month
Moderate risk
D+R+/D–R+	Ganciclovir i.v.Valacyclovir p.o. 1 month	Ganciclovir i.v.Valganciclovir p.o. 3 months
High risk
D+R+/D–R+Exposed to thymoglobulin/OKT3/ATG	Valganciclovir p.o. 1 month+valacyclovir p.o. 2 monthsOR ganciclovir i.v.Valganciclovir p.o. 3 months	Ganciclovir i.v.Valganciclovir p.o. 6 months
D+R–	Ganciclovir i.v.Valganciclovir p.o. 3 or 6 months	Ganciclovir i.v.Valganciclovir p.o. 6 months
Any category receiving rituximab	Not applicable; rituximab was not available	Ganciclovir i.v.Valganciclovir p.o. 6 months

CMV: cytomegalovirus; SGH: Singapore General Hospital

Methods

This is a single-centre before/after retrospective cohort study to evaluate the impact of different CMV prophylaxis protocols on the epidemiology and outcomes of CMV infection in the kidney transplant recipients treated at SGH. The Singhealth Institutional Review Board approved this study (CIRB Ref No. 2018/2367).

Kidney transplant recipients treated at SGH from 2004 to 2008 and from 2010 to 2014 were screened for inclusion and exclusion criteria. A one-year transition period in 2009 was factored into the study design to ensure that the new protocol was more widely implemented. Patients were included if (a) they were aged ⩾18 years at the time of kidney transplant, (b) both donor and recipient CMV serology were available, (c) they complied with the prophylaxis protocol for the designated period and (d) they were followed up at our hospital for at least 24 months. Patients were excluded if they (a) had their transplant performed outside of SGH or Singapore, (b) received a re-transplant during the study period, (c) did not comply with unit prophylaxis protocols and (d) were followed up for <24 months at SGH.

Medical records, laboratory investigations and pharmacy records were reviewed. Patient demographics, transplant data, CMV prophylaxis and clinical outcomes at 24 months were collected and managed using the Research Electronic Data Capture (REDCap) tool hosted at our institution.

The risk of CMV infection was stratified based on CMV serostatus and if lymphocyte-depleting thymoglobulin was given. A recipient is considered high risk if CMV serostatus is donor positive and recipient negative (D+/R–), or if he or she has received thymoglobulin. Risk is considered moderate if CMV serostatus is recipient positive (D+/R+ or D–/R+). This risk stratification applies to both time periods/protocols. The recommended prophylaxis for each risk stratum in the two protocols is detailed in Table 1. Valacyclovir was dosed at 2000 mg q.d.s. in patients with an estimated glomerular filtration rate (eGFR) >75 mL/min, and renally adjusted for those with a lower eGFR. Valganciclovir was dosed at 900 mg o.m. in patients with an eGFR >60 mL/min, and was also renally adjusted for those with a lower eGFR.

CMV infection is defined by the presence of detectable CMV in body fluid or a tissue specimen (with viral culture, antigen tests or nuclear acid amplification tests).^1,11,12 Although recent evidence suggests detection of CMV virus, antigen or DNA in the blood may not necessarily mean active CMV replication,¹² this distinction was not applied for the purpose of this study. The diagnosis of definite and probable CMV end-organ disease has to fulfil preset criteria as defined by Humar et al.^11,13 ‘Delayed-onset’ CMV infections refer to infections occurring one to six months after the cessation of prophylaxis. ‘Late-onset’ CMV infections refer to those occurring more than six months after the cessation of prophylaxis.¹⁴

During the study period, CMV was detected using either the Light Diagnostics CMV pp65 Antigenemia IFA Kit (EMD Millipore, Temecula, CA), or an in-house quantitative real-time CMV polymerase chain reaction. Primary outcomes reviewed include (a) the incidence of any CMV infection occurring over a 24-month follow-up period, (b) incidence of CMV disease (CMV syndrome as well as tissue-invasive disease), (c) recurrence of CMV infection and (d) time to first CMV infection. Tolerability of different CMV prophylaxis was reviewed as a secondary outcome.

Results are expressed as the median and interquartile range (IQR; 25th, 75th percentile) for continuous data and as frequency and percentage for categorical data. The Mann–Whitney U-test was used to compare continuous variables, while Pearson’s chi-square test or Fisher’s exact test was used for categorical variables. Univariable and multivariable logistic regression were performed to estimate the odds ratio (OR) and adjusted OR, respectively, for each risk factor of CMV infection, CMV disease and recurrent CMV infection. Clinically relevant factors with p-values <0.10 on univariable analysis were selected for multivariate analysis to estimate the impact of the CMV prophylaxis protocol on the outcomes. Time to first CMV infection was analysed with the use of the Kaplan–Meier method, and group differences were assessed by the log-rank test and Cox proportional hazards regression model. All analyses were performed using IBM SPSS Statistics for Windows v25.0 (IBM Corp., Armonk, NY). Two-sided p-values <0.05 were considered statistically significant.

Results

There were 192 subjects included in the final analyses; 106 subjects received Protocol 1, and 86 received Protocol 2. Their baseline demographics, transplant characteristics, CMV risk status and prophylaxis are presented in Table 2. Subjects who received Protocol 1 were significantly younger (43.5 years (IQR 35.0–49.0 years) vs. 48.0 years (IQR 39.0–53.3 years), p=0.005) and had a significantly lower Charlson Comorbidity Index (CCI; 2 (2.0–3.0) vs. 2.5 (2.0–3.0), p=0.016). There were also significantly fewer ABO incompatible transplants and expanded criteria donors (ECD) for transplants performed between 2004 and 2008. There was a shift in choice of induction agent used: thymoglobulin was used more frequently between 2004 and 2008, while interleukin-2 receptor antagonists (IL-2RA) such as basiliximab or daclizumab were used more frequently between 2010 and 2014. There was also significant difference in maintenance immunosuppression between the two groups: cyclosporine, azathioprine and mammalian target of rapamycin inhibitors (mTOR inhibitors) were used more frequently in between 2004 and 2008, while more patients received tacrolimus between 2010 and 2014.

Table 2.

Patient characteristics, transplant characteristics, CMV risk and CMV prophylaxis.

	Protocol 1 (2004–2008), N=106	Protocol 2 (2010–2014), N=86	p-Value
Patient demographics
Age (years), median (IQR)	43.5 (35.0–49.0)	48.0 (39.0–53.3)	0.005
Ethnicity, n (%)			0.310
Chinese	84 (79.2%)	58 (67.4%)
Malay	17 (16.0%)	21 (24.4%)
Indian	4 (3.8%)	5 (5.8%)
Other	1 (0.9%)	2 (2.3%)
Male, n (%)	49 (46.2%)	49 (57.0%)	0.149
Co-morbidities, n (%)
Diabetes mellitus	5 (4.7%)	3 (3.5%)	0.733
Ischaemic heart disease	2 (1.9%)	5 (5.8%)	0.246
Congestive cardiac failure	4 (3.8%)	2 (2.3%)	0.693
Cerebrovascular accident	2 (1.9%)	0 (0%)	0.503
Liver disease	0 (0%)	3 (3.5%)	0.088
Cancer	1 (0.9%)	1 (1.2%)	1.00
CCI at time of transplant, median (IQR)	2.0 (2–3)	2.5 (2–3)	0.016
Aetiology of ESRD, n (%)			0.604
Glomerulonephritis	82 (77.4%)	64 (74.4%)
Diabetes mellitus	6 (5.7%)	3 (3.5%)
Hypertension	7 (6.6%)	5 (5.8%)
Other	11 (10.4%)	14 (16.3%)
Type of dialysis prior to transplant, n (%)			0.129
Haemodialysis	95 (89.6%)	70 (81.4%)
Peritoneal dialysis	5 (4.7%)	11 (12.8%)
Pre-emptive transplant	6 (5.7%)	5 (5.8%)
Duration of dialysis (months), median (IQR)	84.4 (11.55–117.9)	95.3 (17.75–122.80)	0.262
Transplant characteristics and immunosuppression
Deceased donor, n (%)	65 (61.3%)	49 (57.0%)	0.558
Living donor, n (%)	41 (38.7%)	37 (43.0%)
Expanded criteria donor, n (%)	7 (10.8%)	16 (32.7%)	0.005
Standard criteria donor, n (%)	58 (89.2%)	33 (67.3%)
ABO incompatible, n (%)	1 (0.9%)	6 (7.0%)	0.047
Number of HLA mismatches, median (IQR)	3 (2–5)	3 (2–4)	0.806
CDC-PRA (%), median (IQR)	0 (0–20)	0 (0–16)	0.712
Induction agent, n (%)			<0.001
IL-2RA	26 (24.5%)	79 (91.9%)
Thymoglobulin	51 (48.1%)	5 (5.8%)
None	29 (27.4%)	2 (2.3%)
Maintenance agents, n (%)
Prednisolone	105 (99.1%)	86 (100%)	1.00
Mycophenolate	97 (91.5%)	84 (97.7%)	0.115
Azathioprine	9 (8.5%)	1 (1.2%)	0.025
Any CNI	93 (87.7%)	85 (98.8%)	0.004
Cyclosporine	76 (71.7%)	39 (45.3%)	<0.001
Tacrolimus	17 (16%)	46 (53.5%)	<0.001
mTOR inhibitor	13 (12.3%)	1 (1.2%)	0.004
CMV serostatus and risk status
CMV serostatus, n (%)			0.185
D–/R–	2 (1.9%)	1 (1.2%)
D+/R+	86 (81.1%)	73 (84.9%)
D–/R+	5 (4.7%)	8 (9.3%)
D+/R–	13 (12.3%)	4 (4.7%)
CMV risk,^a n (%)			<0.001
Low risk (R–)
Intermediate risk (R+)	2 (1.9%)	1 (1.2%)
High risk (D+/R– or	45 (42.5%)	76 (88.4%)
thymoglobulin use in R+)	59 (55.7%)	9 (10.5%)
CMV prophylaxis
Type of CMV prophylaxis, n (%)			<0.001
No prophylaxis	2 (1.9%)	0 (0%)
Valacyclovir-based	67 (63.2%)	0 (0%)
Valganciclovir-based	37 (34.9%)	86 (100%)
Duration of CMV prophylaxis in weeks, median (IQR)	12 (4–12)	13 (13–14)	<0.001

The risk status is designated based on the criteria described in Table 1.

IQR: interquartile range; CCI: Charlson Comorbidity Index; CDC-PRA: complement-dependent panel-reactive antibody; IL-2RA: interleukin-2 receptor antagonist (basiliximab or daclizumab); CNI: calcineurin inhibitor (cyclosporin or tacrolimus); mTOR inhibitors: mammalian target of rapamycin inhibitors (everolimus or sirolimus).

There was no difference in CMV serostatus in the two groups, but there were significantly more patients who were at high risk of CMV in those who received Protocol 1 (59 (55.7%) vs. 9 (10.5%), p<0.001). This was mostly attributed to increased use of thymoglobulin between 2004 and 2008.

It is important to appreciate the difference between the two protocols, as detailed in Table 1. Protocol 1 allowed use of either valacyclovir or valganciclovir; 67 (63.2%) patients received valacyclovir-based prophylaxis. Protocol 2 was exclusively valganciclovir based. The median duration of prophylaxis for patients receiving Protocol 1 was significantly shorter (12 weeks (IQR 4–12 weeks) vs. 13 weeks (IQR 13–14 weeks), p<0.001).

The major CMV outcomes in both groups are presented in Table 3. On univariate analysis, the incidence rates of CMV infections between the two groups were similar: 57 (53.8%) patients in Protocol 1 versus 48 (55.8%) in Protocol 2 (p=0.884). Although the incidence of CMV disease and recurrent CMV infections was higher in patients receiving Protocol 1, this was not statistically significant. There were 91 episodes of CMV reactivation (6 occurred during receipt of prophylaxis, 62 delayed onset and 23 late onset) in patients who received Protocol 1 compared to 61 episodes of CMV reactivation with Protocol 2 (6 during receipt of prophylaxis, 41 delayed onset and 14 late onset; p=0.712). Only one patient on valacyclovir developed breakthrough CMV reactivation. The rest were on valganciclovir prophylaxis. The majority of the CMV infections were asymptomatic viral reactivation picked up on surveillance. Five patients in Protocol 1 and two in Protocol 2 developed CMV syndrome. Only one patient who received Protocol 1 developed tissue-invasive disease with proven CMV retinitis. Two patients (one in each group) developed drug-resistant CMV infection. The incidence of rejection/over-immunosuppression-triggering CMV reactivation in both groups was similar: 28 episodes in Protocol 1 versus 14 episodes in Protocol 2 (p=0.291).

Table 3.

Comparison of major outcomes between protocol 1 and protocol 2, and predictors of CMV infection.

	Protocol 1 (N=106)	Protocol 2 (N=86)	OR (95% CI)	p-Value
CMV infection^a	57 (53.8%)	48 (55.8%)	1.09 (0.61–1.92)	0.884
CMV disease^b	6 (5.7%)	2 (2.3%)	0.40 (0.078–2.02)	0.300
Recurrent CMV episodes	24 (22.6%)	11 (12.8%)	0.50 (0.23–1.09)	0.092

Refers to any level of CMV antigen or polymerase chain reaction detected in blood.

Refers to both CMV syndrome and tissue-invasive CMV disease. For patients receiving Protocol 1, five developed CMV syndrome, and one developed CMV retinitis. Two patients in Protocol 2 had CMV syndrome; there were no cases of tissue-invasive disease.

OR: odds ratio; CI: confidence interval.

The type of CMV prophylaxis protocol was not significantly associated with CMV infection (OR=1.086, 95% confidence interval (CI) 0.613–1.924, p=0.778), even after adjusting for type of donor (deceased vs. living), CMV risk and calcineurin inhibitors (CNI) use (adjusted OR=1.430, 95% CI 0.716–2.854, p=0.310). On multivariate analysis, deceased donor transplantation (OR=1.86, 95% CI 1.02–3.40, p=0.043) and a high CMV risk status (OR=2.138, 95% CI 1.05–4.36, p=0.037) remained significantly associated with CMV infection.

Amongst patients who developed CMV infection, the median time to development of CMV infection from time of transplant was significantly shorter in patients who received Protocol 1 (132 days (IQR 125–139 days) vs. 185 days (IQR 178–192 days), p=0.001). Protocol 1 was associated with an increased risk of earlier CMV infection (hazard ratio (HR)=1.948, 95% CI 1.314–2.887, p=0.001), and the difference remained significant after adjusting for type of donor (living vs. deceased), CMV risk and CNI use (adjusted HR=1.767, 95% CI 1.142–2.734, p=0.011).

Both prophylaxis regimens were relatively well tolerated. None of the patients who received high-dose valacyclovir developed neurotoxicity. Thirteen (12.7%) patients in Protocol 1 and nine (10.6%) in Protocol 2 (p=0.820) developed neutropaenia, but only two patients in Protocol 2 who received a six-month course of prophylaxis had their CMV prophylaxis discontinued prematurely due to cytopaenias. All 22 patients in both time periods who developed neutropaenia received valganciclovir-based prophylaxis and not valacyclovir.

Discussion

We describe a retrospective study comparing two different CMV prophylaxis regimens in renal transplant recipients. Protocol 1, used before 2009, included the use of valacyclovir for the intermediate- and high-risk groups, and duration of prophylaxis was in general shorter. Protocol 2, implemented after 2009, utilised the more potent valganciclovir exclusively, and prophylaxis duration was longer. This change in protocol was largely driven by evidence advocating longer CMV prophylaxis.^10,15

Contrary to our hypothesis that an intensified prophylaxis regimen would reduce the incidence of CMV infection, this was not observed in our study; the rates of CMV infections were similar between both groups. This could be attributed to the heterogeneity of the patients’ baseline characteristics in the two groups. In general, patients who received Protocol 1 were at higher CMV risk, with a greater proportion receiving thymoglobulin, but the incidence of CMV was not increased compared to Protocol 2. The increased number of ABO incompatible transplants, use of ECD and older recipients in Protocol 2 – known risk factors for CMV infections^16–18 – could have blunted the effects of the differences in prophylaxis regimen.

In our study, more than half of the subjects in both time periods (53.8% and 55.8% in Protocols 1 and 2, respectively) experienced at least one episode of CMV reactivation over a 24-month follow-up period post transplant. While this figure appears higher than the reported incidence of CMV infections (~20– 40%) at other centres, we recognise that follow-up duration, diagnostic thresholds and prophylaxis strategies used at different centres were variable and may therefore account for the differences observed.^3,10,19–22 Another reason for the higher reported incidence of CMV infections in our study is attributed to the fact that we had defined CMV infection as the presence of any detectable CMV in body fluid or tissue specimen, and reflected CMV reactivation in the post-transplant recipient. It is important to note that the overall incidence of CMV disease was relatively low (5.7% and 2.3% in Protocols 1 and 2, respectively), and only one patient (who received Protocol 1) developed tissue-invasive disease with CMV retinitis. The majority of the CMV infections in both groups were asymptomatic antigenaemia/viraemia picked up through routine surveillance. The use of universal prophylaxis, regardless of prophylaxis regimen, was likely to have mitigated the risks of severe CMV infections in the two groups.

What we have described in this study is the classic finding of post-prophylaxis CMV reactivation, and this is reflected by significantly shorter time to CMV infection in patients who received Protocol 1. Post-prophylaxis CMV reactivation is not a new finding.^{1,14,16–18,23} Its specific pathophysiology is likely related to the complex interaction between CMV virus and the host, compounded by the use of immunosuppressants. Some experts believe that the lack of reconstitution of CMV-specific cellular immunity in transplant recipients could explain this phenomenon.²⁴ In our multivariate analyses, high CMV risk (determined by CMV D+/R– serostatus and receipt of thymoglobulin) and deceased donor transplant were independently associated with a higher risk of CMV infection, not choice of prophylaxis regimen, consistent with findings observed at other centres.^19,20,25 Prophylaxis strategies alone are insufficient to reduce the incidence of post-transplant infections, and two key areas could be reviewed to improve CMV outcomes: (a) the role of evaluating CMV-specific immunity prior to the discontinuation of antiviral therapy, and (b) the need for individualised immunosuppression dosing as opposed to a protocol-driven approach.

CMV-specific immunoassays have been developed, and they are increasingly being evaluated for clinical use to identify patients who may be at high risk of CMV infection/disease.²⁶ The absence of documented CMV cell-mediated immunity (CMI) at the end of prophylaxis may suggest that the recipient is at higher risk of CMV reactivation/disease and therefore requires close surveillance. Similarly, weak or absent CMV CMI at the end of CMV treatment may suggest that the risk for recurrent disease is higher and may indicate a possible role for secondary prophylaxis. Conversely, in patients with documented CMV CMI, they may spontaneously clear low-level CMV reactivation without the need for systemic antiviral therapy. Serial monitoring of CMV CMI in the right clinical setting may guide clinical management in post-transplant care.^27,28

We observed a high incidence of asymptomatic CMV reactivation upon discontinuation of prophylaxis, and this alludes to the possibility that the current immunosuppression dosing regimen (based on a protocol-driven approach) may be excessive for our local Asian population. The immunological and metabolic risk profile in our patients may be inherently different from the Caucasian population for which current immunosuppression dosing regimens are derived.²⁹ To date, except for the evaluation of trough levels of select immunosuppressants, there is lack of established clinical tools to guide individualisation of immunosuppression therapy for transplant recipients.³⁰ Strategies to reduce the depth of immunosuppression may include (a) the use of a steroid-sparing regimen, (b) reduction of CNI or (c) use of a CNI-sparing regimen.^31–33 However, these strategies are often applied empirically after the diagnosis of CMV reactivation. There is an impetus to develop pharmacogenetic and pharmacogenomic strategies to guide selection of immunosuppression regimen in the era of individualised therapy in transplantation medicine.

This study has several limitations. Because of the retrospective nature of the study spanning over a decade and the evolving clinical practice of transplant medicine,^32,34–37 our patient population in both groups was heterogenous, and there were baseline differences in recipient demographics, transplant and immunological risks, as well as maintenance immunosuppression. Therefore, we cannot be sure if the difference or lack thereof in CMV infections was due to the inherent differences between the two groups, or if there were truly no difference between the two different prophylaxis regimens. The small number of subjects in the study may limit our ability to detect statistically significant differences. Finally, excess immunosuppression, graft rejection or co-infections are factors that could potentially influence the incidence of CMV infections in our study, but these parameters could not be clearly ascertained in this retrospective study.

Within the limitations of this study, there are practical applications for some of our findings. We compared two different universal prophylaxis protocols: a shorter course of valacyclovir-/valganciclovir-based prophylaxis regimen versus a longer course of valganciclovir-based prophylaxis regimen with no demonstrable difference in the epidemiology and outcomes of CMV infections between the two groups. While a valganciclovir-based prophylaxis regimen remains the standard of care in intermediate- to high-risk kidney transplant recipients as advocated by major society guidelines,³⁵ a valacyclovir-based protocol may be a reasonable alternative, especially in resource-limited settings, given its comparable efficacy, tolerability and cost-effectiveness.^9,36 In our study, breakthrough CMV reactivation while on valacyclovir prophylaxis was rare. Although neurotoxicity has been reported in patients receiving high-dose valacyclovir,³⁷ this was not observed in our study. Where available, we would recommend the use of CMV prophylaxis with either valganciclovir or valacyclovir, given the high rates of CMV infection and disease (~70% and 26–52%, respectively) in the absence of prophylaxis.³⁸

Post-prophylaxis CMV infections are not uncommon, regardless of valganciclovir or valacyclovir universal prophylaxis. Vigilance for CMV reactivation should be exercised, and we recommend a period of CMV surveillance after universal prophylaxis is discontinued, especially for patients at high risk of CMV.

Conclusion

Intensifying CMV prophylaxis by using valganciclovir exclusively and prolonging the course was associated with longer time to first CMV infection but not overall reduction in incidence of CMV infection at 24 months. Valacyclovir may be a reasonable alternative to valganciclovir, especially in resource-limited settings or in situations where valganciclovir cannot be tolerated. After prophylaxis is discontinued, CMV surveillance and careful titration of immunosuppression are adjunct strategies for the prevention of CMV infection/disease.

Footnotes

Acknowledgements

M.T. would like to express her thanks to J.C., T.K., S.T. and H.Q.Y. for their guidance and valuable feedback during the course of this project. The authors would like to express their thanks to the transplant coordinators for their help in data collection.

Authors’ contributions

T.K., M.T. and J.C. researched the literature and conceived the study. T.K. and J.C. were involved in protocol development. M.T. and J.C. did data collection. Data analysis was done by J.C. and H.Q.Y. M.T. wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Availability of data and materials

The data sets generated are available from the authors.

Ethical approval

The Singhealth Institutional Review Board approved this study (CIRB Ref No. 2018/2367).

Informed consent

Waiver of informed consent for this audit was approved by the SingHealth Centralised Institutional Review Board (CIRB Ref: 2018/2367), as this was a clinical audit of routine clinical care, where participants were not subjected to additional risks or burdens beyond usual clinical practice.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

ORCID iD

Terence Yi Shern Kee

References

Kotton

Kumar

Caliendo

, et al. The Third International Consensus Guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018; 102: 900–931.

Van Ree

De Vries

APJ

Zelle

, et al. Latent cytomegalovirus infection is an independent risk factor for late graft failure in renal transplant recipients. Med Sci Monit 2011; 17: 609–617.

Selvey

Lim

Boan

, et al. Cytomegalovirus viraemia and mortality in renal transplant recipients in the era of antiviral prophylaxis. Lessons from the western Australian experience. BMC Infect Dis 2017; 17: 1–10.

Erdbrügger

Scheffner

Mengel

, et al. Long-term impact of CMV infection on allografts and on patient survival in renal transplant patients with protocol biopsies. Am J Physiol Ren Physiol 2015; 309: F925–F932.

Razonable

Humar

Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13: 93–106.

Falagas

Vardakas

KZ.

Anti-cytomegalovirus prophylaxis in solid-organ transplant recipients. Clin Microbiol Infect 2006; 12: 603–605.

Paya

Humar

Dominguez

, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004; 4: 611–620.

Asahi

Tsutsui

Wakasugi

, et al. Valacyclovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol 2009; 16: 457–160.

Reischig

Kacer

Jindra

, et al. Randomized trial of valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation. Clin J Am Soc Nephrol 2015; 10: 294–304.

10.

Humar

Lebranchu

Vincenti

, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant 2010; 10: 1228–1237.

11.

Humar

Michaels

American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant 2006; 6: 262–274.

12.

Ljungman

Boeckh

Hirsch

, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis 2017;64:87–91.

13.

Razonable

Humar

Cytomegalovirus in solid organ transplant recipients – guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33: e13512.

14.

Razonable

Blumberg

EA.

It’s not too late: a proposal to standardize the terminology of ‘late-onset’ cytomegalovirus infection and disease in solid organ transplant recipients. Transpl Infect Dis 2015; 17: 779–784.

15.

Doyle

Warburton

Goral

, et al. 24-Week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course. Transplantation 2006; 81: 1106–1111.

16.

Choi

Han

DJ.

Ongoing higher infection rate in ABO-incompatible kidney transplant recipient: is it a serious problem? A single-center experience. Ann Surg Treat Res 2016; 91: 37–44.

17.

Noble

Jouve

Malvezzi

, et al. Transplantation of marginal organs: immunological aspects and therapeutic perspectives in kidney transplantation. Front Immunol 2019; 10: 3142.

18.

Hemmersbach-Miller

Alexander

Pieper

, et al. Age matters: older age as a risk factor for CMV reactivation in the CMV serostatus-positive kidney transplant recipient. Eur J Clin Microbiol Infect Dis 2020; 39: 455–463.

19.

Chiasakul

Townamchai

Jutivorakool

, et al. Risk factors of cytomegalovirus disease in kidney transplant recipients: a single-center study in Thailand. Transplant Proc 2015; 47: 2460–2464.

20.

De Matos

Meyer

Washington de Mendonça Lima

Cytomegalovirus infection after renal transplantation: occurrence, clinical features, and the cutoff for antigenemia in a university hospital in Brazil. Infect Chemother 2017; 49: 255–261.

21.

Chawla

Ghobadi

Mosley

, et al. Oral valganciclovir versus ganciclovir as delayed pre-emptive therapy for patients after allogeneic hematopoietic stem cell transplant: a pilot trial (04-0274) and review of the literature. Transpl Infect Dis 2012; 14: 259–267.

22.

Arthurs

Eid

Pedersen

, et al. Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation. Clin Infect Dis 2008; 46: 840–846.

23.

Legendre

Pascual

Improving outcomes for solid-organ transplant recipients at risk from cytomegalovirus infection: late-onset disease and indirect consequences. Clin Infect Dis 2008; 46: 732–740.

24.

Manuel

Husain

Kumar

, et al. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study. Clin Infect Dis 2013; 56: 817–824.

25.

Browne

Young

Dunn

, et al. The impact of cytomegalovirus infection ⩾1 year after primary renal transplantation. Clin Transplant 2010; 24: 572–577.

26.

Khanna

Immune monitoring of infectious complications in transplant patients: an important step towards improved clinical management. J Clin Microbiol 2018; 56: e02009-17.

27.

Kumar

Mian

Singer

, et al. An interventional study using cell-mediated immunity to personalize therapy for cytomegalovirus infection after transplantation. Am J Transplant 2017; 17: 2468–2473.

28.

Andreani

Albano

Benzaken

, et al. Monitoring of CMV-specific cell-mediated immunity in kidney transplant recipients with a high risk of CMV disease (D+/R−): a case series. Transplant Proc 2020; 52: 204–211.

29.

Zsom

Wagner

Fülöp

Minimization vs tailoring: where do we stand with personalized immunosuppression during renal transplantation in 2015?

World J Transplant 2015; 5: 73–80.

30.

Zaza

Granata

Tomei

, et al. Personalization of the immunosuppressive treatment in renal transplant recipients: the great challenge in ‘omics’ medicine. Int J Mol Sci 2015; 16: 4281–4305.

31.

Pascual

Quereda

Zamora

, et al. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation 2004; 78: 1548–1556.

32.

Krüger

Banas

Hoffmann

Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2008; 358: 2518–2519.

33.

Schena

Pascoe

Alberu

, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009; 87: 233–242.

34.

Webster

Playford

Higgins

, et al. Interleukin 2 receptor antagonists for renal transplantation recipients: a meta-analysis of randomized trials. Transplantation 2004; 77: 166–176.

35.

Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9: S1–S155.

36.

Matter-Walstra

Greiner

Cusini

, et al. Stringent adherence to a cytomegalovirus-prevention protocol is associated with reduced overall costs in the first 6 months after kidney transplantation. Transpl Infect Dis 2015; 17: 342–349.

37.

Lowance

Neumayer

H-H

Legendre

, et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. New Eng J Med 1999; 340: 1462–1470.

38.

Kamar

Mengelle

Esposito

, et al. Predictive factors for cytomegalovirus reactivation in cytomegalovirus-seropositive kidney-transplant patients. J Med Virol 2008; 80: 1012–1017.

A single-centre observational study comparing the impact of different cytomegalovirus prophylaxis strategies on cytomegalovirus infections in kidney transplant recipients

Abstract

Background/objective:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Results

Discussion

Conclusion

Footnotes

Acknowledgements

Authors’ contributions

Availability of data and materials

Ethical approval

Informed consent

Conflict of interest

Funding

ORCID iD

References