a comparison of different valgancyclovir …manu.edu.mk/prilozi/40_3/4.pdf · method in reducing...

MASAМАНУ

CONTRIBUTIONS. Sec. of Med. Sci., XL 3, 2019ПРИЛОЗИ. Одд. за мед. науки, XL 3, 2019

ISSN 1857-9345UDC: 616.132-007.271-089.843 616.61-089.843-085.281.8.035.4

ABSTRACT

Introduction: Cytomegalovirus (CMV) is the most common opportunistic infective pathogen in kidney transplant recipients. Valganciclovir (VAL) is commonly used for prophylaxis, especially in high-risk recipients. Generic VAL formulations have become available, but the data about their safety and efficacy are lacking.Methods: Consecutive de novo kidney transplant patients were randomized to generic VAL Valganciklovir Teva® (VT group)(24 patients) or Alvanocyte® (A group), Alvogen (19 patients) or to Valcyte® (V group), Roche (23 patients) in a 18-month open-label study. Universal prophylaxis was used for 6 months after the transplantation. CMV DNA levels were measured at 1,3,6,9,12 and 18 months after the transplantation. All positive measurements of CMV DNA were recorded.Results: Groups did not differ regarding the clinical characteristics or the risk for developing CMV infection in the post-transplant period. CMV replications were most common at 9 months after the transplantation with rates of 9% for the V, 13% for the VT and 26% for the A group (p=0.26). At 12 months, positive CMV DNA was recorded in 22%, 8% and 11 % of patients taking V, VT and A, respectively (p=0.37). Rates of biopsy-proven acute rejection, adverse events, and serious adverse events were similar for all formulations. Lymphocele occurred most commonly in the V group (35%) compared to 17% in VT and 17% in the A group (p=0.23). One patient from each of the A and VT groups developed CMV disease. Additionally, they were the only two patients with CMV DNA copies above 656 IU/ml. Glomerular fil-tration rates were similar in all groups at all time points, while proteinuria was significantly higher at 12 months in patients who received V 0.32 g/day (0.18 – 0.42), compared to patients on VT 0.2 (0.1 – 0.2), or A 0.2 (0.2 – 0.3), p=0.04. Conclusion: Valgancyclovir efficacy and safety in this limited data set is similar with early administration of V, VT and A after kidney transplantation. Additional studies aimed at elucidating the effectiveness of this treatment regimen in patients who are at high risk for developing CMV infection are necessary to draw further conclusions.

Keywords: CMV, prophylaxis, generic, valganciclovire

Corresponding author: Prof. Nikolina Basic-Jukic, MD, PhD, Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Kispaticeva 12, Croatia, e-mail: [email protected]

1 Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Croatia 2 Faculty of Medicine, University of Zagreb, Croatia 3 Department of Urology, University Hospital Centre Zagreb, Zagreb, Croatia

Nikolina Basic-Jukic1,2, Vesna Furic-Cunko1, Tvrtko Hudolin2, 3, Zoran Zimak3, Jason Kirincich2, Zeljko Kastelan2, 3

A COMPARISON OF DIFFERENT VALGANCYCLOVIR FORMULATIONS IN THE UNIVERSAL 6-MONTH PROPHYLAXIS AGAINST CMV INFECTION IN RENAL TRANSPLANT RECIPIENTS: A RANDOMIZED SINGLE-CENTRE STUDY

48 Nikolina Basic-Jukic et al.

INTRODUCTION

Cytomegalovirus (CMV) is the most com-mon opportunistic infective pathogen in kidney transplant recipients. Infection may occur by en-dogenous reactivation of CMV in the recipient, it may be transmitted by the allograft or it can be acquired de novo from the general population. Clin-ical presentations include asymptomatic viraemia, CMV viral syndrome and CMV tissue invasive disease [1]. CMV has a number of indirect immu-nomodulatory effects that can be deleterious for kidney transplant recipients such as an increased risk for acute rejection and an increased risk for other opportunistic infections. Additionally, CMV leads to increased rates of morbidity and mortality in this patient population as a consequence of its role in chronic allograft injury, malignancy forma-tion and accelerated atherosclerosis [2].

Antiviral prophylaxis against CMV is consid-ered to be a standard of care in high-risk patients (donor +ve – recipient -ve), though there is no uni-form consensus for other constellations [3]. The current approach of using antiviral drugs for CMV prophylaxis and early treatment in conjunction with improved diagnostic methods is a well-established method in reducing the incidence of CMV infec-tions and its indirect effects [4].

Valganciclovir (VAL) is commonly used for prophylaxis, especially in high-risk recipients. Ge-neric VAL formulations have become available, but the data about their safety and efficacy is lacking. Herein, we investigate the efficacy and safety of two generic VAL formulations in a randomized open-label single-centre prospective study.

PATIENTS AND METHODS

Study designAn observational, prospective, open-label, sin-

gle-centre study was conducted in which generic VAL formulations were compared to the originator for universal prophylaxis against CMV infection after renal transplantation. Primary endpoints were efficacy (prevention of CMV infection or disease) and safety. Three groups of patients were created based on the VAL formulation (Alvanocyte group (A), Valgancyclovire Teva (VT) group and Valcyte (V) group, respectively).

Study populationConsecutive patients who received a renal al-

lograft at our institution between January 2016 and April 2017 were included in the investigation. Eligi-ble patients were 18 years or older and scheduled to receive a kidney transplant from either living related or deceased donor. Patients younger than 18 years, patients who refused to participate in the study, lost the allograft, died or were lost to follow-up less than 3 months after transplantation were excluded from the analysis (Fig 1). Data from donors and recipients were collected from the hospital’s medical records and charts. The following data were obtained: date of birth; age at transplantation; graft number; date of transplantation; weight and height at transplant; maximum panel reactive antibody (PRA) status; recipient CMV serology status; human leukocyte antigen (HLA) mismatches; occurrence of acute rejection; immunosuppressive therapy; duration of hospitalization after the surgery; number of rehospi-talizations; different complications; allograft failure; patient outcome (death). Donor source; donor age; cause of death; serum creatinine and donor CMV serology status were recorded. Donor was defined as expanded criteria donor based on the definition of Metzger et al. [5]

The study was conducted in compliance with Good Clinical Practice Guidelines. The study pro-tocol was approved by the hospital’s Ethics Com-mittee. The procedures followed in the trial were in accordance with the Declaration of Helsinki. In-formed consent has been obtained from the patients prior to involvement.

ImmunosuppressionAll patients received triple therapy with in-

duction. Basiliximab was used in 58 patients (88 %), and polyclonal antibodies in 8 (12 %) patients. Triple therapy included steroids in all patients, a calcineurin inhibitor (cyclosporine in 5 and tacroli-mus in 61 patients) and an antiproliferative drug (mycophenolate mofetil in 58 and everolimus in 8 patients). Tacrolimus trough levels were titrated to a level of 5-10 μg/L. Biopsy-proven T cell mediated rejection episodes were managed with intravenous methylprednisolone pulses. Filgrastim was used if the neutrophil count was less than 500/L.

CMV evaluationDonor CMV serology status was obtained

from donor reports and recipient CMV serology status from individual patient records. CMV DNA

49GENERIC VALGANCICLOVIRE IN CMV PROPHYLAXIS

plasma viral load testing was performed at the De-partment of microbiology, using the COBAS® Am-pliPrep/COBAS® TaqMan® CMV Test (Roche). CMV DNA was assessed at 1, 3, 6, 9 and 12 months after the transplantation. Replication was considered to be present if CMV DNA was positive (>137 cop-ies/ml), and significant if the number of copies was above 656 [6].

Prophylaxis and treatment of CMVUniversal prophylaxis with VAL was used in

all recipients. After providing informed consent, pa-tients enrolled in the study received VAL from the second day after the transplantation if CMV IgG positive, or have started with VAL before transplan-tation if CMV IgG is negative. The dose of VAL was individually adjusted based on the allograft function. Prophylaxis lasted 6 months.

Patients were diagnosed as having an asymp-tomatic CMV infection if they were positive for CMV DNA but without any symptoms. CMV viral syndrome or invasive disease was diagnosed on the basis of having symptoms together with a positive CMV DNA test result. In cases of CMV infection, patients received VAL treatment with a dose titrated to the corresponding allograft function. In cases of CMV disease along with VAL treatment, the dose of MMF was reduced. The antiviral treatment usually lasted for 3 months and was discontinued after 2 consecutive negative CMV DNA tests.

AssessmentsStudy visits were conducted on the day be-

fore transplantation (baseline) and 1, 3, 6, 9, 12 and 18 months after transplantation. At each visit we performed physical examination, laboratory meas-urements and CMV DNA. Any medical problem was recorded during visits. Renal function assess-ment included creatinine clearance and proteinuria in 24-h urine. Safety was evaluated throughout the study by laboratory investigations and clinical as-sessments designed to determine the incidence of adverse events, infections and malignancies.

Data were recorded and entered in the elec-tronic database.

Statistical analysisData are expressed as the mean ± SD for con-

tinuous variables or as the median and interquartile range (IQR). Comparisons between the groups were performed with the use of chi-squared test, Kruskal Wallis or Fisher’s exact test as appropriate. Logistic regression analysis was used to determine risk fac-tors for CMV infection.

Fig. 1. Study flowchart. Patients included in the study according to prevention strategy.

One hundred seventeen (117) patients received a renal allograft, of whom 49 (41.8%) refused to participate in the study. One patient died one month post-transplant and one lost her allograft, thus 66 patients were included in the study. Patients were randomized to Valcyte®, Valgancyclovire Teva® or Alvanocyte® for prevention of CMV infection.

RESULTS

Patient and donor characteristicsA total of 66 patients were included in the

investigation and were followed for 18 months. Table 1. shows baseline demographic character-istics of recipients and donors based on the val-ganciclovire formulation used for CMV proph-ylaxis. Patient demographics and transplant characteristics were comparable. Induction and maintenance immunosuppression regimens were similar. 5 patients were CMV IgG negative be-fore renal transplantation and received a kidney allograft from a CMV IgG positive donor.


Table 1. Patients' characteristics. V, Valcyte; VT, Valganciclovir Teva; A, Alvanocyte; CMV, cytomegalovirus; ADPKD, autosomal dominant polycystic kidney disease; PD, peritoneal dialysis; HD, haemodialysis; TX, renal transplantation; HLA, human leukocyte antigen.

Variable V group(n=23)

VT group(n=24)

A group(n=19) P*

CMV IgG negative 1 (4%) 3 (12%) 2 (10%) 0.66Gender [n(%)]Male 17 (74) 16 (67) 12 (63) 0.79Age [Median (25%-75%)] 58 (47 – 67) 59 (41 – 65) 55 (45 – 64) 0.93†

Primary kidney disease [n(%)]Nephroangiosclerosis 6 (26) 4 (17) 4 (21) 0.54ADPKD 2 (9) 4 (17) 3 (16) 0.74Glomerulonephritis 6 (26) 4 (17) 4 (21) 0.64Pyelonephritis 1 (4) 2 (7) 1 (5) 0.29Diabetic nephropathy 3 (13) 4 (17) 3 (16) 0.57Unknown 5 (22) 6 (25) 4 (21) 0.78Type of dialysis [n(%)]HD 7 (33) 6 (26) 6 (32) 0.80PD 9 (43) 14 (61) 10 (53)HD+PD 5 (24) 3 (13) 3 (16)Age at start of dialysis [Median (25%-75%)] 57 (42 – 63) 55 (44 – 61) 52 (43 – 59) 0.94†

Dialysis vintage (months) [Median (25%-75%)] 15.8 (11.2 – 63.8) 32.3 (18.6 – 43.1) 21.1 (10.7 – 33.5) 0.48†

Number of Tx [Median (min-max)] 1 (1 – 2) 1 (1 – 2) 1 (1 – 1) 0.41†

HLA Mismatch0 2 (9) 0 1 (5)

0.87

1 1 (4) 2 (8) 02 4 (17) 7 (29) 4 (21)3 11 (47.8) 10 (41.7) 8 (42.1)4 4 (17.4) 4 (16.7) 5 (26.3)5 1 (4.3) 0 1 (5.3)6 0 1 (4.2) 0

Donor characteristics are presented in Table 2.

Table 2. Donor characteristics. V, Valcyte; VT, Valganciclovir Teva; A, Alvanocyte; *χ2 test; †Kruskal Wallis test

Variable V group(n=23)

VT group(n=24)

A group(n=19) P*

Gender [n(%)]male 3 (13) 10 (42) 7 (37) 0.08

Age [Median (25%-75%)] 51 (45 – 60) 51.5 (37 – 57) 50 (44 – 54) 0.77†

CMV IgG [n(%)]

Negative 2 (8.6) 3 (12.5) 4 (21) 0.19Donor type [n(%)]

Deceased 23 (100) 23 (96) 19 (100) >0.99Living 0 1 (4) 0Expanded criteria donor [n(%)] 5 (22) 4 (17) 5 (26) 0.76

CMV infection and/or diseaseThe cumulative incidence of CMV

infection (any number of CMV DNA copies) over the observed period was 25.75% and of CMV disease 3%. One patient from the A and one from the VT group developed CMV disease after treatment discontinuation. The patients had 3710 and 4660 copies of CMV DNA, respectively.

One of them was CMV IgG negative before transplantation. They were the only two patients with CMV DNA levels above 656 IU/ml.

Rehospitalizations were more frequent in the group of patients with CMV infection/disease (77%) compared to 53% in patients without CMV infection (p=0.09). None of the parameters were predictive for the development of CMV infection in our cohort (Table 3).


Table 3. Univariate regression analysis for prediction of CMV infection

β Wald P OR 95% CIRecipientsAge 0.13 0.34 0.56 1.01 0.97 – 1.06Gender - male 0.90 2.38 0.12 2.46 0.78 – 7.73Type of diaylsis - PD 0.20 0.09 0.76 1.22 0.34 – 4.30 HD + PD -0.47 0.26 0.61 0.62 0.09 – 3.92Age at dialysis 0.01 0.36 0.55 1.01 0.97 – 1.06Dialysis vintage -0.01 0.88 0.35 0.99 0.96 – 1.01MM A 0.51 1.37 0.24 1.7 0.71 – 3.92MM B 0.30 0.43 0.51 1.35 0.55 – 3.32MM DR 0.07 0.03 0.87 1.1 0.44 – 2.67MM total 0.30 1.29 0.26 1.36 0.80 – 2.29Induction - ATG 0.63 0.64 0.42 1.89 0.39 – 8.91CMV IgG negative 0.31 0.44 0.47 1.78 0.39 - 4.46Th - Tacrolimus -0.72 0.55 0.46 0.49 0.07 – 3.21V – VT -0.29 0.18 0.67 0.75 0.19 – 2.89A 0.27 0.15 0.69 1.31 0.34 – 5.01DonorsAge 0.03 1.43 0.23 1.03 0.98 – 1.08Gender - male 0.06 0.009 0.93 1.06 0.32 – 3.54CMV IgG positive 0.42 0.47 0.49 1.52 0.46 – 5.002Living donor 20.16 5.9·10-6 0.99 5.68·106 -

None of the patients treated with everolimus developed CMV infection.

Table 4. shows the cumulative incidence of CMV infection taking into account the antiviral drug used.

Table 4. Cumulative incidence of CMV infection based on the antiviral prophylaxis. TX, renal trans-plantation; CMV, cytomegalovirus. V, Valcyte; VT, Valganciclovir Teva; A, Alvanocyte; Number of cases (%).*Fisher’s exact test

Time after TX (months) V group(n=23)

VT group(n=24)

A group(n=19) P*

1 0 0 1 (5) 0.293 1 (4) 0 0 0.396 0 1 (4) 0 0.419 2 (9) 3 (13) 5 (26) 0.2612 5 (22) 2 (8) 2 (11) 0.3718 1 (4) 1 (4) 0 0.41

Patient and allograft survivalNone of the patients died over the observed

period. Table 5 shows creatinine clearance over the follow-up period based on valganciclovire usage for CMV prophylaxis. Table 5. Creatinine clearance over the follow-up pe-riod based on valganciclovire used for CMV prophy-laxis. V, Valcyte; VT, Valganciclovir Teva; A, Alvano-cyte; *Kruskal Wallis test


VT group(n=24)

A group(n=19) P*

1 65 (38.8 – 94.8) 64.5 (33.75 – 78.5) 54 (36 – 64.5) 0.513 68 (48.5 – 88) 71 (42 – 84) 54 (41 – 87.5) 0.686 59 (51.8 – 81.8) 77 (38.75 – 89.5) 63 (48.5 – 80.5) 0.929 58 (47.5 – 87.3) 82 (42.25 – 94.75) 72 (45 – 94) 0.7712 61 (53 – 84.8) 72 (45 – 91) 71 (48 – 82) 0.9018 65 (46.5 – 78.5) 54.5 (46.25 – 88) 67 (57.5 – 85.5) 0.60


Table 6 shows proteinuria over the fol-low-up period based on valganciclovire usage for CMV prophylaxis. Proteinruia is expressed as proteins in daily urine.

Table 6. Proteinuria over the follow-up period based on valganciclovire used for CMV prophylaxis. V, Valcyte; VT, Valganciclovir Teva; A, Alvanocyte; *Kruskal Wallis test


VT group(n=24)

A group(n=19) P*

1 0.3 (0.2 – 0.6) 0.3 (0.18 – 0.4) 0.2 (0.2 – 0.3) 0.603 0.3 (0.2 – 0.3) 0.25 (0.14 – 0.41) 0.3 (0.1 – 0.4) 0.986 0.3 (0.2 – 0.5) 0.2 (0.1 – 0.4) 0.2 (0.2 – 0.4) 0.309 0.3 (0.16 – 0.48) 0.2 (0.2 – 0.3) 0.2 (0.1 – 0.4) 0.3612 0.23 (0.16 – 0.39) 0.2 (0.1 – 0.3) 0.2 (0.1 – 0.3) 0.5718 0.32 (0.18 – 0.42) 0.2 (0.1 – 0.2) 0.2 (0.2 – 0.3) 0.04

There was no difference between the groups until 12 months when significantly high-er, although low-grade, proteinuria was observed in the V group.

Complications and clinical events after transplantation

Table 7 shows the complications occurring after renal transplantation taking into account the antiviral drug used.

Table 7. Complications after renal transplan-tation depending on the antiviral drug used. V, Val-cyte; VT, Valganciclovir Teva; A, Alvanocyte; *χ2 test; †Kruskal Wallis test

Time after TX V group(n=23)

VT group(n=24)

A group(n=19) P*

Length of hospitalization [Median (25%-75%)] 12 (10 – 20) 13 (10 – 16) 14 (9 – 17) 0.89†

Rehospitalisation [n(%)] 17 (74) 13 (54) 9 (48) 0.18Number of rehospitalizations [Median (25%-75%)] 1 (0 – 2) 1 (0 – 2) 0 (0 – 3) 0.67†

Biopsy proven acute rejection [n(%)] 2 (9) 2 (8) 0 0.42Leukopenia[n(%)] 3 (13) 5 (21) 1 (5) 0.33Timing of leukopenia (months)[Median (25%-75%)] 3.6 (2.7 – 7.8) 6.9 (1.1 – 11.7) 2.9 (n=1) 0.55†

Need for filgrastim 3 (13) 2 (8) 0 0.28BK viruria 8 (34) 12 (50) 7 (37) 0.52JC viruria 5 (22) 3 (13) 1 (5) 0.29Fungal infection 0 1 (4) 0 0.41Lymphocele 8 (35) 4 (17) 3 (16) 0.23

There was no difference in renal function or rates of biopsy-proven acute rejection, graft loss, opportunistic infections, or new-onset diabetes af-ter transplantation. The VT group had more frequent leukopenias; however, premature valganc iclovir discontinuation was more frequent in the V group while they developed leukopenia earlier (median 3,6 months) than patients from VT group (median 6,9

months) (p=0,33). Additionally, more patients from the V group required filgrastim.

Patients treated with A spent a longer amount of time in the hospital immediately after transplant, but required less rehospitalizations than patients treated with V or VT. BK viruria was more frequent in the VT group. Biopsy proven acute rejection occurred in two patients from each of the V and VT groups, but was


not noted in patients treated with A. None of afore-mentioned differences reached statistical significance.

There was no difference regarding the occur-rence of surgical complications, malignancies, car-diovascular problems or new onset diabetes after transplantation between the groups.

DISCUSSION

A recent meta-analysis which included 40 trials and more than 5000 patients confirmed that pre-emptive therapy and antiviral prophylaxis are equally successful in preventing major complica-tions of CMV infection in kidney allograft recipients, including CMV disease, allograft loss and patient death [7]. Despite the proactive approach, CMV disease remains an important problem after organ transplantation, with a surprisingly high mortality rate that was demonstrated in a study of D+R+-trans-plant patients with CMV viraemia [8]. Gancyclovire and more recently, valganciclovire have successfully been used for prophylaxis and treatment of CMV infection. Given the importance of CMV infection for outcomes after renal transplantation, introduction of generic VAL formulations have been a matter of concern in the transplant community.

We conducted a randomized study with the primary aim to demonstrate the non-inferiority of generic VAL formulations regarding the safety and efficacy in renal transplant recipients. Patients were randomized to V, VT or A with universal prophy-laxis for 6 months. CMV replications were most common 9 months after the transplantation; 9% for V, 13% for VT and 26% for A (p=0.26); while at 12 months reactivations were recorded in 22%, 8% and 11% of patients (p=0.37), respectively. Rates of biopsy-proven acute rejection, adverse events, and serious adverse events were similar for all for-mulations. Lymphocele most commonly occurred in the V group (35%) compared to 17% in VT and 17% in the A group (p=0.23). One patient from the A and one from the VT group developed CMV dis-ease. Glomerular filtration rates were similar in all groups, while proteinuria was significantly higher at 12 months in patients who received Valcyte 0.32 g/day (0.18 – 0.42), compared to patients on VT 0.2 (0.1 – 0.2), or A 0.2 (0.2 – 0.3), p=0.04.

While the latest CMV assays are able to detect low-level viraemia, it remains unknown whether low-level viraemia is clinically significant. We re-corded any viremia above 137 copies/ml as positive.

It is important to stress that there is no recognized cut-off for the initiation of antiviral medications [9]. In a study by Martin-Gandul et al. CMV cop-ies greater than 3983 IU/mL were associated with a higher predictive value than lower cut-offs [10]. While a lower level of measured CMV copies was not found to be correlated with a risk of developing invasive disease, there is concern for the existence of indirect effects. However, no definite recommen-dations regarding antiviral therapy for this indication exist [11, 12]. Contrary to previous results, Selvey et al. found that low level CMV viraemia (≥656 cop-ies/ml) was associated with an increased incidence of death, which suggests vigilant treatment when CMV viraemia reaches these levels [6]. Based on this approach, only two of our patients (3%) had significant CMV viremia, demonstrating efficacy of all VAL formulations and of universal prophylaxis in prevention of CMV replication.

Patients from the V group had significantly higher proteinuria one year post-transplant for un-clear reasons. Recently, low-grade proteinuria has gained more attention for its prognostic implications as it may occur before the development of donor-spe-cific antibodies, predict the development of diabetes and cardiovascular events, and is associated with reduced graft and patient survival [13]. Two main mechanisms may be responsible for the develop-ment of proteinuria: tubular proteinuria due to isch-emic-reperfusion injury, rejection, or toxic agents and glomerular proteinuria caused by recurrent or de novo glomerulonephritis, transplant glomerulopathy, chronic rejection, or CNI toxicity [14]. Thus, our findings deserve further investigations.

Prophylaxis has been associated with a sig-nificant increase in late-onset CMV infections and more drug-related side effects (leukopenia and neutropenia) than the pre-emptive strategy [7]. In our cohort, 13.6% of patients developed leukope-nia, and 7.5% developed neutropenia. Patients from the V group developed leukopenia earlier (median 3,6 months) than patients from the VT group (median 6,9 months) (p=0,33), and more frequently required valganciclovir discontinuation and use of filgrastim. In the study by Liam et al. the cumulative incidence of leukopenia at 6 months post-transplant was 39.3% (11.0% for neutropenia) [15]. Timing of CMV infection after cessation of valgancyclovir differs among the groups but is not statistically significant. Namely, the V group tended to develop CMV infection at 12 months while patients from the A group developed CMV infection at 9 months. Only two patients devel-


oped CMV disease, one was IgG negative before transplantation. None of the patients who received everolimus developed CMV infection, which is supported by previous studies [16].

There are some strengths and limitations to our study. It is the first randomized head-to-head study to compare different valganciclovire formulations with important results regarding the efficacy and safety of generic antivirals for the broad transplant community. However, it is a sin-gle-centre study with small number of patients. Only 5 patients were CMV IgG negative before transplantation, reflecting the fact that 88.2% of haemodialysis patients in Croatia are CMV IgG positive (17). Additionally, we did not perform electrophoresis for urine proteins which limits our ability to make conclusions about the origin and aetiology of higher level proteinuria in the originator group.

CONCLUSIONS

We found that generic valganciclovire for-mulations (Valganciclovir Teva and Alvanocyte) are not inferior regarding the safety and efficacy to originator Valcyte. All formulations had excellent efficacy, with only 3% of patients from our cohort developing significant CMV replication. Howev-er, further examination in high risk patients and in larger cohorts is required.

REFERENCES

1. De Keyzer K, Van Laecke S, Peeters P, Vanhold-er R. Human cytomegalovirus and kidney trans-plantation: a clinician’s update. Am J Kidney Dis. 2011; 58(1): 118–126.

2. Freeman RB., Jr. The ‘indirect’ effects of cyto-megalovirus infection. Am J Transplant. 2009; 9: 2453–2458.

3. Hodson EM, Ladhani M, Webster AC, Strippoli GF, Craig JC. Antiviral medications for prevent-ing cytomegalovirus disease in solid organ trans-plant recipients. Cochrane Database Syst Rev. 2013: CD003774.

4. Humar A, Lebranchu Y, Vincenti F, 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.

5. Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Merion RM. Expanded criteria donors for kidney transplantation. Am J Transplant. 2003; 3 Suppl 4: 114–125.

6. Selvey LA, Lim WH, Boan P, et al. Cytomega-lovirus 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): 501.

7. Florescu DF, Qiu F, Schmidt CM, Kalil AC. A di-rect and indirect comparison meta-analysis on the efficacy of cytomegalovirus preventive strategies in solid organ transplant. Clin Infect Dis. 2014 Mar; 58(6): 785–803.

8. Harvala H, Stewart C, Muller K, Burns S, Mar-son L, MacGilchrist A, Johannessen I. High risk of cytomegalovirus infection following solid or-gan transplantation despite prophylactic therapy. J Med Virol. 2013; 85(5): 893–898.

9. Razonable RR, Hayden RT. Clinical utility of viral load in management of cytomegalovirus infection after solid organ transplantation. Clin Microbiol Rev. 2013; 26: 703–727.

10. Martin-Gandul C, Perez-Romero P, Sanchez M, et al. Spanish network for research in infectious D: determination, validation and standardization of a CMV DNA cut-off value in plasma for preemptive treatment of CMV infection in solid organ trans-plant recipients at lower risk for CMV infection. J Clin Virol. 2013; 56: 13–18.

11. Razonable RR, Humar A. Cytomegalovirus in sol-id organ transplantation. Am J Transplant. 2013; 13: 93–106.

12. Torre-Cisneros J, Aguado JM, Caston JJ et al. Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESI-TRA-SEIMC/REIPI recommendations. Trans-plant Rev (Orlando) 2016; 30: 119–143.

13. Halimi JM. Low-grade proteinuria and microalbu-minuria in renal transplantation. Transplantation. 2013; 96(2): 121–130.

14. Ponticelli C, Graziani G. Proteinuria after kidney transplantation. Transpl Int. 2012; 25(9): 909–917.

15. Liang X, Famure O, Li Y, Kim SJ. Incidence and Risk Factors for Leukopenia in Kidney Trans-plant Recipients Receiving Valganciclovir for Cytomegalovirus Prophylaxis. Prog Transplant. 2018; 28(2): 124–133.

16. Tedesco-Silva H, Pascual J, Viklicky O, et al. Safety of Everolimus With Reduced Calci-neurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study. Transplantation. 2019 Feb 19.

17. Vilibic-Cavlek T, Kolaric B, Bogdanic M, Tabain I, Beader N. Herpes Group Viruses: a Seropreva-lence Study in Hemodialysis Patients. Acta Clin Croat. 2017; 56(2): 255–261.


Резиме

СПОРЕДБА НА РАЗЛИЧНИТЕ ФОРМУЛАЦИИ НА ВАЛГАНЦИКЛОВИР ВО УНИВЕРЗАЛНАТА ШЕСТМЕСЕЧНА ПРОФИЛАКСА НАСПРОТИ ИНФЕКЦИЈАТА СО ЦМВ КАЈ ПРИМАТЕЛИТЕ НА БУБРЕЖНИ ТРАНСПЛАНТИ: РAНДОМИЗИРАНА СТУДИЈА НА ЕДЕН ЦЕНТАР

Николина Башиќ-Јукиќ1, 2, Весна Фуриќ-Чунко1, Твртко Худолин2, 3, Зоран Зимак3, Џејсон Киринцич2, Жељко Каштелан2, 3

1 Оддел за нефрологија, артериска хипертензија, дијализа и трансплантација, Универзитетски болнички центар Загреб, Загреб, Хрватска2 Медицински факултет, Универзитет во Загреб, Загреб, Хрватска3 Оддел за урологија, Универзитетски болнички центар Загреб, Загреб, Хрватска

Вовед: Цитомегаловирус (ЦМВ) е најчестиот можен инфективен патоген кај примателите на бубрежен трансплант. Valganciclovir (VAL) најчесто се користи за профилакса, особено кај примателите со висок ризик. Општите формулации на ВАЛ станаа достапни, но недостасуваат податоците за нивната безбедност и ефикасност.

Методи: Последователните de novo пациенти со бубежен трансплант беа рандомизирани на генерички VAL Valganciklovir Teva® (група VT) (24 пациенти) или Alvanocyte® (група А), Alvogen (19 пациенти) или Valcyte® (група V), Roche (23 пациенти) во 18-месечна отворена студија. Универзалната профилакса се користеше шест месеци по трансплантацијата. ДНК-ни-воата на ЦМВ беа мерени на 1, 3, 6, 9, 12 и 18 месеци по трансплантацијата. Беа запишани сите позитивни мерења на ДНК на ЦМВ.

Резултати: Групите не се разликуваа во однос на клиничките карактеристики или ризикот за развој на инфекција со ЦМВ во периодот по трансплантацијата. Репликациите на ЦМВ беа најчести девет месеци по трансплантацијата со стапки од 9% за V, 13% за VT и 26% за групата А (p = 0,26). На 12 месеци, позитивна ДНК на ЦМВ е забележана кај 22%, 8% и 11% од паци-ентите што земаа V, VT и A, соодветно (p = 0,37). Стапките на акутно отфрлање докажано со биопсија, несаканите дејства и сериозните несакани дејства беа слични за сите формулации. Лимфоцелата се јави најчесто во групата V (35%) споредено со 17% кај VT и 17% во групата А (p = 0,23). Еден пациент од секоја од групите А и VТ ја разви болеста ЦМВ. Покрај тоа, тие беа единствените двајца пациенти со примероци на ДНК со ЦМВ над 656 IU/ml. Стапките на гломеруларна филтрација беа слични кај сите групи во сите временски точки, додека протеину-ријата беше значително повисока на 12 месеци кај пациентите што примаа V 0,32

Заклучок: Ефективноста и безбедноста на валганцикловирот во овој ограничен комплет податоци е слична со раната администрација на V, VT и A по трансплантацијата на бубрег. Не-опходни се дополнителни студии насочени кон разјаснување на ефективноста на овој режим на третман кај пациентите со висок ризик за развој на инфекција на ЦМВ, за да се извлечат дополнителни заклучоци.

Клучни зборови: ЦМВ, профилакса, генерични, валганцикловир

a comparison of different valgancyclovir …manu.edu.mk/prilozi/40_3/4.pdf · method in reducing...

Documents