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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 2  |  Page : 104-110

Evaluation of alternate-day valganciclovir prophylaxis for cytomegalovirus disease prevention in moderate risk renal transplant patients: A retrospective observational study


Department of Nephrology, KG Hospital and PG Institute, Coimbatore, Tamil Nadu, India

Date of Submission27-Jul-2020
Date of Decision12-Dec-2020
Date of Acceptance31-Dec-2020
Date of Web Publication30-Jun-2021

Correspondence Address:
Dr. Puneet Bhuwania
Department of Nephrology, KG Hospital and PG Institute, Coimbatore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_84_20

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  Abstract 

Background: Despite valganciclovir (VGCV) being the recommended agent for Cytomegalovirus (CMV) disease prevention, its optimal dose that maintains parity between the efficacies, toxicity profile, and most importantly, the cost has yet to be established. This study is the first to evaluate alternate day versus daily dose of VGCV prophylaxis in CMV prevention in moderate risk renal transplant patients (RTR). Materials and Methods: A single center, retrospective analysis of ninety-nine moderate risk RTR was done. The study participants received VGCV 450 mg/day (n = 49) versus VGCV 450 mg on alternative days (n = 50) for 90–100 days; as a prophylactic strategy against CMV disease. The primary endpoint was CMV disease incidence at 6 months. Graft survival, biopsy-proven rejection, hematological adverse events, opportunistic infections (OIs), and mortality have also been evaluated. Results: CMV disease occurrence at 6 months was zero in both the groups. Immunosuppression (induction and maintenance) were alike in both the groups except for higher tacrolimus trough levels in the 2nd month (P = 0.023) and lower mycophenolate acid area under curve levels in alternate-day group (P = 0.046). No difference was noted in biopsy-proven rejection, graft loss, mortality, and OIs, but leukopenia was more in patients receiving daily VGCV (P ≤ 0.001), a multivariate logistic regression revealed a higher incidence of leukopenia in the daily group (P = 0.02; odds ratio, 13.6, 95% confidence interval 1.51–122.37). Conclusions: Alternate-day VGCV dosing provides similar efficacy as daily dosing in CMV prevention in D+/R + RTR with reduced leukopenia incidence and significant cost-benefit.

Keywords: Cluster of differentiation 3 count, cytomegalovirus, mycophenolic acid area-under-curve, tac trough, vanganciclovir


How to cite this article:
Bhuwania P, Veerappan I, Sethuraman R. Evaluation of alternate-day valganciclovir prophylaxis for cytomegalovirus disease prevention in moderate risk renal transplant patients: A retrospective observational study. Indian J Transplant 2021;15:104-10

How to cite this URL:
Bhuwania P, Veerappan I, Sethuraman R. Evaluation of alternate-day valganciclovir prophylaxis for cytomegalovirus disease prevention in moderate risk renal transplant patients: A retrospective observational study. Indian J Transplant [serial online] 2021 [cited 2021 Jul 24];15:104-10. Available from: https://www.ijtonline.in/text.asp?2021/15/2/104/319892


  Introduction Top


Cytomegalovirus (CMV) being a well-established opportunistic infection (OI) confronted in the posttransplant setting, its impact on morbidity, graft survival and mortality, in renal transplant recipients is very significant.[1],[2] Anti-CMV Immunoglobulin G (IgG) is detected in plasma in renal donors with prior CMV exposure when being evaluated for transplantation and so it is one of the multiple factors that can influences CMV emergence, others being CMV serological status of the recipient, the usage of preemptive therapy or prophylaxis and immune-suppressants.[3] Delayed graft function, OIs, and acute rejection have been linked to CMV.[3] To diminish the risks to the allograft and the patient, suitable surveillance and prevention measures must be employed. The aim of prophylaxis is to administer antiviral therapy for a fixed period, while the basis of preemptive therapy is to monitor viral load and initiate antiviral therapy if viral load is high.[2] Valganciclovir (VGCV) prophylaxis has been proven to be effective in CMV prevention in high-risk patients with donor positive/recipient negative antibody status (D+/R−) and moderate-risk patients with donor negative/recipient positive antibody status (D−/R+) or patients with donor positive/recipient positive antibody status (D+/R+) in both high (900 mg) and lower (450 mg) doses.[4],[5],[6] At our center most of the renal transplant recipients are D+/R+ except deceased transplant patients in whom the donor CMV status is not known. VGCV was developed to overcome the shortcomings of intravenous and oral ganciclovir and is a prodrug of the same.[7],[8],[9] A 900 mg daily dose of VGCV provides proportional ganciclovir plasma levels to those achieved with intravenous ganciclovir at a dose of 5 mg/kg.[7],[8],[9],[10],[11],[12],[13],[14],[15] VGCV has many adverse effects which include diarrhea, leukopenia, and fever.[16],[17] It's important to estimate the glomerular filtration rate (GFR) and accordingly modify VGCV dose.[16],[17] A multivariate analysis included 8 trials with 450 mg VGCV (1531 patients) and 12 trials with 900 mg VGCV (1543 patients).[18] The high-risk group (D+/R−) showed equal efficacy of 900 mg VGCV and 450 mg VGCV (statistical power: 97%) for CMV prophylaxis.[18] A 3-time higher incidence of leukopenia and 2-times higher risk of biopsy-proven acute rejection (BPAR) was seen in the dose of 900 mg VGCV compared with 450 mg daily VGCV.[18] VGCV prophylaxis for 100 days after transplant has been recommended, as it has been proven to be efficacious in averting CMV disease in moderate-risk patients.[16],[17] We have hypothesized in view of the very low incidence of CMV in our population/center that alternate-day dose VGCV 450 mg for 3 months, may have a similar prophylactic effect in Moderate risk renal transplant patients (RTR) against CMV disease. Here, we retrospectively investigated RTR for safety and efficacy of CMV chemo-prophylaxis with 450 mg alternate-day dosing versus 450 mg daily dosing of VGCV in the first 3 months posttransplant which was changed due to the very low incidence of CMV in our center.


  Materials and Methods Top


Patients and data collection

A single center retrospective observational evidenced-based study utilizing our institutional electronic medical record system for retrospective analysis of the data which was internal board approved to identify all RTR starting from January 2017–2019. Patients who underwent kidney Transplant from January 2017 to December 2017, were given VGCV as 450 mg/day (49 patients) as a part of prophylactic therapy for 90–100 days, and those who underwent kidney transplant from January 2018 to January 2019, the VGCV dose was decreased to 450 mg every alternative day (50 patients) for the same duration as above. The low incidence of CMV seen in the previous year in our center was trigger leading to reduction in the dose of VGCV but strict monitoring for drug compliance of the same using measures such as pill counting was done during each visit. All the recipients, live or deceased were complement-dependent cytotoxicity crossmatch negative. None of the patients underwent human leukocyte antigen (HLA) desensitization before transplant. ABO-incompatible recipients, who underwent desensitization according to institutional protocol, were also included in our study along with complete HLA mismatch patients. Details of CMV status of donor and recipient, prescribed CMV prophylaxis, and investigation results were noted from our clinical records. The primary endpoint was CMV infection incidence till 6 months posttransplant defined as (i) Positive CMV Deoxyribonucleic acid (DNA) determination by polymerase chain reaction (PCR), (ii) Evidence of CMV with positive immunohistochemistry staining or viral inclusions on histology. The secondary endpoints included adverse drug effects like leukopenia episodes during the period of prophylaxis. Leukopenia attacks (i.e., total White blood cell counts <4000 cells/μL) were monitored and were appropriately treated, initially with alteration of the medication in question i.e., VGCV dose reduction, mycophenolate mofetil (MMF) dose reduction, trimethoprim/sulfamethoxazole (TMP/SMX) dose reduction and if not responding to the above administering granulocyte colony-stimulating factor (G-CSF) treatment (0.5–2 ug/kg/day based on response) and temporarily stoppage of offending medications.[19],[20] Outcomes such as BPAR, OI, graft survival and mortality were also explored. A total of 99 individuals were included for analysis and evaluation.

Cytomegalovirus disease

CMV antibody qualitative IgG titer done as a part of the pretransplant evaluation, determined the CMV serostatus of the donor and recipient. As Per our institutional protocol, CMV DNA by PCR was done to confirm CMV infection/disease only in the presence of clinical suspicion by the treating consultant in the posttransplant setting; hence PCR testing for CMV DNA was not performed routinely. CMV disease was defined as a positive PCR which included either a viral syndrome (e.g., malaise, fever, associated leukopenia, and thrombocytopenia) or as a tissue invasive disease presenting as pneumonitis (hypoxia), colitis (diarrhea), hepatitis (transaminitis), and neurological (encephalitis, retinitis) as described by Ljungman et al. and used in other publications.[21],[22],[23]

Immunosuppression and cytomegalovirus prophylaxis

As per our institutional protocol, all transplant recipients including live or deceased kidney transplant recipients received a single dose of rabbit Anti-thymocyte globulin (r-ATG)/ATG– Fresenius (ATG-F) IV (2–5 mg/kg) as a part of induction therapy along with methylprednisolone 500 mg IV on the postoperative days 0, 1, 2 days respectively followed by cluster of differentiation– 3 (CD3) counts on postoperative day 3 to evaluate the efficacy of the induction therapy but none of the patients received an additional dose of the r-ATG/ATG-F following the CD-3 levels. Maintenance Immunosuppression included a combination of calcineurin inhibitor i.e., Tacrolimus (0.15 mg/kg) or cyclosporine (3–5 mg/kg), Anti-proliferative agent i.e., MMF (30 mg/kg) and prednisolone (initially initiated at 20 mg/day then was tapered to 2.5–5 mg/day at around 4 weeks posttransplant and remained at 2.5–5 mg/day during the study period. Target trough levels tacrolimus and for cyclosporine were 10–15 and 150–300 ng/mL, respectively, during the first 3 post-transplant months. For Pneumocystis carinii pneumonia prophylaxis, TMP/SMX 480 mg single-strength tablets were administered daily. All the rejection episodes were biopsy proven and were classified according to the Banff criteria.[24] Acute (T-cell) cellular rejections were treated with intravenous bolus dose of methyl–prednisolone 500 mg/day for 3 days, escalating maintenance immunosuppressants and for steroid-resistant rejection; r-ATG was given (1 mg/kg daily for 5–7 days). Acute (B-cell) antibody-mediated rejections were treated with therapeutic plasma exchange, after every plasma exchange a dose of intravenous Ig (100 mg/kg), and rituximab after completion of plasma exchange (375 mg/m2 per dose to maintain a CD19 count of zero). Our patients were initiated on VGCV prophylaxis after the 1st week posttransplant and were continued the same for 90–100 days posttransplant (i.e., 450 mg on alternate day vs. 450 mg/day) with compliance to the drug evaluated on every visit.

Statistical analysis

Univariate analysis was conducted for each factor assumed to be related to the group. Independent sample t-test and Mann–Whitney U-test were used to test the association of continuous variables between groups. Association between categorical factors and groups was tested using the Chi-square test. P value of 0.05 was fixed for any statistical significance. Multivariate logistic regression was used to assess the adjusted effect of the factors on the incidence of Leucopoenia. Factors that are statistically significant at a 10% level of significance from univariate analysis and clinically significant were included in the model.

Patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

Indian Council of Medical Research/Good Clinical Practice guidelines were followed. Patients were enrolled for the study after clearance from the institute ethics committee. (ECR/213/Inst/TN/2013/RR-16). Study was carried out as per Declaration of Helsinki.


  Results Top


Patients

A total of 99 patients were enrolled and evaluated retrospectively in our centre (daily dose group n = 49; alternate-day group n = 50) Baseline transplant characteristics and demographics are reported in [Table 1]. The alternate day dose group contained significantly more living donors (40 patients vs. 20 patients; P ≤ 0.001). Population were younger in alternate day dose group (39.8 ± 12.2 vs. 47.9 ± 13.34 years; P = 0.002) which was probably due to higher live related transplants in alternate day group (80% vs. 40.8%; P ≤ 0.001). Similar weight in both groups were seen (59.4 ± 15.1 vs. 62.7 ± 12.8 kg; P = 0.256). All recipients (live or deceased) belonged to moderate risk group with regards to CMV sero-status. With regards to immunosuppression, r-ATG/ATG-F was used as induction in the both the groups (3.56 ± 0.80 vs. 3.36 ± 0.60 mg/kg; P = 0.16) with a CD3 levels checked on postoperative day 3 being numerically higher in alternate day group (182 vs. 155 cells/mL; P = 0.061). The type of maintenance immune-suppressants used was similar in the two groups which included early steroid tapering to lowest possible dose. The alternate day group had significantly lower dose of steroid used at baseline maintenance (39 [78%] vs. 29 [59.2%] P = 0.044). However, the alternate day group population had a higher tacrolimus trough levels versus the daily group in all the 3 months but significantly higher in the 2nd month (10.3 ± 2.35 vs. 9.4 ± 2.5 ng/mL; P = 0.075, 10.8 ± 2.14 vs. 9.7 ± 2.03 ng/mL; P = 0.023 and 10.1 ± 1.85 vs. 9.2 ± 2.5 ng/mL; P = 0.053, respectively), and but also had lower mycophenolic acid (MPA) levels (area-under-curve [AUC]) levels done in the 1st month as compared to daily group population (31.0 ± 10.11 vs. 37.8 ± 15.52 mg.h/l; P = 0.046) [Table 2].
Table 1: Demographics and baseline characteristics of the study population

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Table 2: Characteristic of immunosuppressive therapy in patients during follow-up

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Efficacy

Cytomegalovirus disease

Patients who were suspected to have CMV disease according to clinical findings and subsequently tested for the CMV occurrence were more in the daily dose group (five patients vs. 13 patients) but none of them tested positive hence zero cases were reported [Table 3].
Table 3: Safety and efficacy endpoints

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Safety

[Table 3] reports the safety outcomes of the drug. In spite of the intended duration of prophylaxis being only 90–100 days, Leukopenia, was lower in the group receiving alternate day dose; (10% vs. 42.9%; P ≤ 0.001). Despite higher rates of leukopenia in the daily dose group, VGCV discontinuation did not occur. The incidence of fever, diarrhea and dyspnea were similar (8% vs. 4.1% P = 0.414; 4% vs. 4.1% P = 0.984; 4% vs. 4.1% P = 0.984) respectively in both the groups. A multivariate logistic regression model was constructed to control for risk factors in the groups and when adjusted for age, type of transplant (live related), Induction dose, tacrolimus trough levels in 2nd month, MPA-AUC levels, and biopsy-proven rejection in patients receiving daily dose of VGCV, there was a 13 times high risk of developing leukopenia as compared to alternate-day dose group [Table 4].
Table 4: Result of multivariate logistic regression assessing the factors of leukopenia

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Graft outcomes

All inclusive, the BPAR in both groups were similar (24% vs. 26.5%; P = 0.369) and similar acute tubular necrosis due to unknown etiology (10% vs. 8.2%; P = 0.369). None of the biopsy showed immunohistochemistry staining or viral inclusions suggestive of CMV. While receiving prophylaxis, renal function on alternate day dose recipients evaluated by serum creatinine and estimated GFR (eGFR), had a significantly higher values at 1, 3 and 6 months, (80.6 ± 28.44 vs. 62.0 ± 27.40 mL/min; P = 0.001, 69.5 ± 21.67 vs. 54.3 ± 22.16 mL/min; P = 0.001, 77.6 ± 22.00 vs. 62.7 ± 25.75 mL/min; P = 0.003 respectively) [Table 5].
Table 5: Graft outcomes

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Other outcomes

The percentage of patients with confirmed OI, other than CMV disease, at 6 months posttransplant were equivalent between the groups (alternate day-dose = 28% vs. daily-dose = 24.5%; P = 0.692). The mortality rates of both the groups was also comparable at 6 months post-transplant i.e., (4% vs. 4.1%; P = 0.558) [Table 3].


  Discussion Top


Antiviral prophylaxis use has been recommended as a way of CMV disease prevention in Moderate risk RTR by many international consensus guidelines.[25],[26] The recommended prophylactic dose and agent for moderate risk RTR is 900 mg/day of VGCV for a duration of 100 days which can be extended duration up to a maximum of 6 months in patients undergoing pretransplant desensitization or receiving an anti-lymphocyte antibody as an induction.[25],[26] Neither of the given guidelines accepts the prescription of alternate day dose of VGCV; however, nearly 30%–40% of centers have reported using the low-dose regimen of 450 mg/day in the moderate-risk population.[27] The very low incidence of CMV disease in our population/centre indicates that VGCV prophylaxis for 3 months at either 450 mg on alternative day or 450 mg/day can be effective in CMV Infection or disease prevention. In this analysis, neither of the VGCV regimens offered any benefit on graft or patient survival and acute rejection rates. These results are in complete contrast to the meta-analysis performed by Kalil et al.,[28] which showed a higher risk of acute rejection with higher-doses of VGCV using an adjusted indirect comparison. Many pharmacokinetic (PK) studies have demonstrated that GCV exposure levels at oral GCV 3 g/day dose can be achieved by low-dose VGCV. These analyses inferred that low-dose VGCV can provide enough drug levels for effective prophylaxis against CMV.[29],[30],[31] Kalil et al. demonstrated in a meta-analysis, that equivalent efficacy for CMV prophylaxis can be provided by either of the low or high-dose VGCV regimens (97% statistical power).[28] With growing clinical evidence which is supported by the PK data for the use of low-dose VGCV, the Moderate risk population can be reasonably evaluated by this regimen of alternate day dose versus daily dose. With regards to other outcomes, the rates of leucopoenia were higher in group receiving daily antiviral prophylaxis and this could be the reason for temporary VGCV discontinuation. We did not notice a significant difference in terms of other OI, reported as polyoma virus, varicella zoster, herpes simplex and fungal infections between the groups. Despite the availability of VGCV as a generic 450 mg tablet at a mean wholesale cost of 450 Rupees. Purely based on cost, alternate-day dose VGCV can provide medication-related savings of nearly 20,000 Rupees per patient over 3 months and if the need of G-CSF therapy at around 2500–4000 Rupees per drug depending on dose is considered, the alternate-day dose of VGCV therapy is associated with significant medication cost-saving benefits. These savings are of utmost importance in a developing country; where drug nonadherence related graft dysfunction is a common occurrence of which high medication costs is a known risk factor.[32],[33],[34]


  Conclusions Top


As stated previously, little evidence favoring low-dose VGCV for prophylaxis is available, none of the studies have used such low doses of 450 mg on alternative days. We could therefore conclude that an alternate-day dose of VGCV may provide sufficient CMV prophylaxis in D+/R+ RTR. It was also noted that alternate-day dose VGCV was associated with less leukopenia and so lower G-CSF use and hence lesser discontinuation of the drug. As the data collected did not evaluate the type of infections and hence no assumptions or conclusions could be drawn from the observations on OIs. Although a formal pharmaco-economic evaluation was never completed in our analysis, an undeniable superiority of the alternate day VGCV regimen was its cost advantage.

Limitations

The study's limitations have been acknowledged by us.

Data collection was done in a retrospective manner and had a very small sample size.

The analysis was done in a small window (i.e., at the posttransplant days 30, 60, 90, 180 [±10 days]) or during the OP visits, laboratory values were evaluated. This could have led to missed periods of under or over-immunosuppression in each group and an under-representation of hematologic adverse events. In patients whose renal functions fluctuate, especially RTR, renal dosing of medication is a highly specific task that requires the use of other clinical elements beyond serum creatinine and eGFR. These clinical judgments are not only limited to VGCV but applied to all medications that require dose adjustment, no matter what regimen was used for the patients. Evaluation of concomitant medications including nonimmunosuppressive agents was not undertaken. Finally, As CMV events are rare in our transplant population and testing was done based on clinical judgment; it limited our ability to perform more substantial statistical analysis to find more differences across the treatment groups. Although we have regulated for all baseline transplant and demographic characteristics of the patients that can be statistically different between our groups, the possibility of the presence of residual confounding factors is still present.

Future directions

The performance of a randomized, blinded, and prospective analysis is truly needed to evaluate the other differences between these 2 dosing regimens and also between the standard of care and alternate-day dosing. A formal pharmaco-economic analysis would also be required to be done as a part of any further evaluation to prove its potential cost-saving benefit which would be associated with an alternate-day dose regimen.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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