Objectives: Prophylaxis for cytomegalovirus infection is highly recommended for kidney transplant reci­pients. The use of daily 900 mg valganciclovir is the usual prophylactic dose, whereas 450 mg daily is under investigation. We evaluated the outcome of using 2 different doses of valganciclovir prophylaxis for cytomegalovirus infection after kidney transplant.

Materials and Methods: We randomized kidney transplant recipients (1:1) to receive 450 mg daily valganciclovir (group 1) or 900 mg daily valganciclovir (group 2) for the first 6 months after kidney transplant. Serologically, all patients were at moderate risk for cytomegalovirus infection. Patients were studied for incidence of cytomegalovirus disease, leukopenia attacks, rejection episodes, and graft outcomes for 1 year.

Results: Demographic features of group 1 (98 patients) and group 2 (98 patients) were comparable. More than 50% of patients received thymoglobulin induction therapy without difference between the groups. There were more leukopenia attacks in group 2 (P = .03) requiring higher doses of granulocyte colony-stimulating factor (P = .03). Group 2 patients received lower doses of mycophenolate mofetil (P= .04) and required reduced doses of valganciclovir (P = .045). Compared with group 1, the high-dose group developed numerically more rejection episodes (P = .057) and more cytomegalovirus infections requiring full treatment (P = .17). Graft and patient outcomes were satisfactory in both groups.

Conclusion: Six months of low-dose valganciclovir prophylaxis for intermediate-risk kidney transplant recipients was as effective as high-dose valganciclovir with a better safety profile.

Key words : Immunosuppression, Renal transplantation, Rejection

Introduction

Cytomegalovirus (CMV) is one of the common viral infections after kidney transplant.¹ Exposure to CMV results in detectable anti-CMV immunoglobulin G in the plasma in most kidney donors and recipients before transplant.¹ Cytomegalovirus can result in multisystem disease, as well as many clinically important events such as fever and neutropenia.¹ Furthermore, CMV has a number of indirect effects on kidney transplant recipients, including reduced long-term patient survival, increased risks of other opportunistic infections, acute and chronic graft rejection, allograft dysfunction, and increased total costs.^2,3 Without prophylaxis, most CMV disease occurs during the first 3 months after transplant, when patients are receiving intensive immuno­suppressive agents to prevent graft rejection.^4-6 The risk of CMV infection after transplant is highly dependent on donor (D) and recipient (R) serostatus and the intensity of the immunosuppression regimen.^1,7-9 Cytomegalovirus-seronegative recipients of CMV-seropositive donors (D+/R−) are at the highest risk, whereas D+/R+ or D−/R+ transplants are at moderate risk.^7-9 Valganciclovir has an extended prophylactic effect against other viruses that also require prophylaxis (eg, herpes simplex and varicella-zoster virus infections).1 At our center, most kidney transplant recipients are at moderate risk for CMV infection and they receive universal prophylaxis due to its ease of administration, effectiveness, and prophylaxis against other viruses and possibly other bacterial and protozoan infections.^6-12

Valganciclovir is a valine ester prodrug of ganciclovir that was developed to overcome the limitations of oral and intravenous ganciclovir.^10-12 A single daily 900-mg oral dose provides comparable plasma ganciclovir exposures to those achieved with 5 mg/kg intravenous ganciclovir.^10-18 Valganciclovir has significant adverse effects, including diarrhea, fever, and leukopenia.^19,20 It is crucial to directly measure estimated glomerular filtration rate (eGFR) and adjust valganciclovir dose accordingly.^19,20 As advised in the literature and by the manufacturer, the Cockcroft-Gault formula is considered an appropriate and practical method to estimate GFR to decide for valganciclovir dose.^19-21

Cytomegalovirus disease resistance has been reported as a result of lower valganciclovir dose given after underestimation of GFR by Modification of Diet in Renal Disease formula, which responded well after adjustment of the valganciclovir dose to the Cockcroft-Gault formula.²² In a multivariate analysis, 12 trials with 900 mg valganciclovir (1543 patients) and 8 trials with 450 mg valganciclovir (1531 patients) were included.23 In the high-risk group (D+/R−), 900 mg valganciclovir showed equivalent efficacy to 450 mg valganciclovir (statistical power: 97%) for CMV universal prophylaxis.²³ A dose of 900 mg valganciclovir was significantly associated with a 3-time increase in the risk of leukopenia and 2-time increase in the risk of rejection compared with 450 mg valganciclovir.²³

It is recommended to administer valganciclovir prophylaxis for 200 days after transplant, which is proven to be more efficacious than a 100-day course in preventing CMV disease in high-risk patients.^19,20 We hypothesized that low-dose valganciclovir, at 450 mg/d for 6 months, may have the same pro­phylactic effect against CMV disease in intermediate-risk kidney transplant recipients, with a better safety profile and patient compliance. Here, we prospectively investigated kidney transplant recipients for efficacy and safety of CMV chemo­prophylaxis with low-dose (450 mg/d) versus high-dose (900 mg/d) valganciclovir for the first 6 months after transplant. The primary efficacy parameter was the proportion of patients who developed CMV disease (either CMV syndrome or tissue invasive disease) up to 1 year posttransplant. Patients were assessed for early-onset and late-onset CMV disease, number and consequences of leukopenia attacks, associated infections, rejection episodes, and graft and patient outcomes. Safety profile was evaluated by the regular clinical and laboratory assessment during hospital stay and outpatient visits.

Materials and Methods

From 2010 through 2013, we enrolled 201 kidney transplant recipients in this study. Using simple randomization method, we sequentially randomized our patients (1:1) to receive universal anti-CMV prophylaxis as low-dose valganciclovir (450 mg) in group 1 (100 patients) or high-dose valganciclovir (900 mg) in group 2 (101 patients) for 6 months posttransplant (treatment phase; Figure 1). All patients provided signed informed consent. The study was conducted in full accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines and adhered with local and national regulatory requirements and laws. Eligible patients were only adult kidney transplant recipients (> 18 y old) who could tolerate oral valganciclovir within 1 week posttransplant. Delayed graft function was defined as dialyzed patients during the first week posttransplant.24 Slow graft function was defined as serum creatinine >250 μmol/L at day 5 posttransplant without dialysis.²⁴ Doses were given according to eGFR calculated by Cockcroft-Gault formula. Patients with eGFR < 10 mL/min or who required dialysis had their study medication interrupted but could resume medication once eGFR increased to ≥ 10 mL/min provided they have not missed > 14 consecutive days of study medication or more than 21 days in any given 28-day period.

Our immunosuppression protocol comprised anti-lymphocyte antibody induction using 5 daily doses of rabbit antithymocyte globulin (Sanofi US, Bridgewater, NJ, USA) as 1 mg/kg (maximum 150 mg/dose) or 2 doses of IL-2 receptor blocker (Basiliximab; Novartis, Inc., Basel, Switzerland) as 20 mg each at the time of transplant and on day 4 posttransplant based on immunologic risk stratification. Thymoglobulin dose was reduced according to the manufacturer’s recom­mendations when leukopenia or thrombocytopenia developed. All patients received 1 g methyl­prednisolone sodium succinate intravenously intraoperatively. Maintenance therapy comprised prednisone (60 mg/d gradually reduced to 0.4 mg/kg at 1 mo and to 5-10 mg/d at 6 mo posttransplant), 1 g mycop­henolate mofetil (MMF) twice daily for all patients, and a calcineurin inhibitor. All rejection episodes were biopsy proven and treated according to the Banff criteria of 2011.²⁵ Acute cellular rejection was treated with an intravenous bolus of 1 g/d methyl­prednisolone for 3 days and/or thymoglobulin (1.5 mg/kg daily for 7-14 d) for steroid-resistant rejection. Antibody-mediated rejection was treated with plasma exchange, intravenous immunoglobulin (2 g/kg), and rituximab (375 mg/m² per dose to maintain a CD19 count of zero). Patients who received thymoglobulin were given secondary anti-CMV prophylaxis for 6 weeks in a dose according to the patient’s group.

Patients were monitored daily during hospital stay and then at each outpatient visit with complete blood picture, serum creatinine, eGFR, liver function tests (serum bilirubin, albumin, and liver enzymes), and drug levels. Quantitative real-time polymerase chain reaction (PCR) for CMV DNA was tested at our center’s immunology laboratory at the time of transplant and at 1, 2, 3, 6, 9, and 12 months after transplant with the same assay. Patients with significant CMV-PCR titer associated with any sign of CMV disease were treated with therapeutic doses of valganciclovir or intravenous ganciclovir according to the clinical situation. Treatment was given for at least 3 weeks or until the CMV-PCR became negative according to weekly monitoring. This was followed by secondary valganciclovir prophylaxis (900 mg daily) to complete a total period of 3 months. Cytomegalovirus syndrome was defined as CMV viremia identified by quantitative PCR and at least 1 of the following: fever ≥ 38°C, new onset severe malaise, leukopenia on 2 successive measurements separated by at least 24 hours (defined as a white blood cell count of < 4.0 cells/L if presymptomatic count was ≥ 4.0 cells/L or a decrease of > 20% if the presymptomatic count was < 4.0 cells/L), atypical lymphocytes of ≥ 5%, throm­bocytopenia (defined as a platelet count of <100 cells/L if the prior count was ≥ 120 cells/L or a decrease of >20% if the prior count was < 100 cells/L), or elevation of hepatic transaminases to ≥ 2 × upper limit of normal. Tissue invasive CMV was defined as evidence of localized CMV infection (CMV inclusion cells, in situ detection of CMV antigen, cell culture by immunostain, or DNA by hybridization) in a biopsy or other appropriate specimen (eg, bronchoalveolar lavage or cerebrospinal fluid), and symptoms of organ dysfunction. Sustained significant viremia without any clinical or laboratory evidence of CMV disease were treated as CMV syndrome. Definitions of CMV disease were consistent with the current American Society of Transplantation guidelines for use in clinical trials.²⁶

Leukopenia attacks (defined as above as those that required manipulation of the study medication or immunosuppressive drugs during the treatment phase) were monitored for time after transplant, MMF dose reduction, valganciclovir dose reduction, and requirement for granulocyte colony-stimulating factor (G-CSF) treatment. Mild leukopenia attacks that did not require any intervention were ignored. When leukopenia developed, supportive G-CSF dose was given (0.5-1.5 ug/kg/d according to the response) to increase the absolute neutrophil count above 1 cell/L. Persistent leukopenia was managed by extra doses of G-CSF, reduction of MMF dose, valganciclovir, trimethoprim/sulfamethoxazole, and other offending drugs that contribute to leukopenia and can be stopped temporarily.^27,28

Details of patients who developed CMV disease or rejection episodes during the study period were recorded. Associated infections were also recorded if they necessitated hospital admission.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA). Sample size was calculated to accept a marginal error of 6.6% with confidence interval 95% in a normally distributed population. The null hypothesis of no difference in the proportion of patients responding in each treatment group was tested using the stratified Cochran-Mantel-Haenszel analysis for the primary endpoint. No adjustments were made for multiple statistical testing. Variables and means were compared using paired sample t test, independent sample t test, chi-squared test, Fisher exact test, and ANOVA as appropriate. Results are expressed as means ± standard deviation, and differences were considered significant at P ≤ .05. Graft and patient survivals were summarized using life table methods and Kaplan-Meier curves and tested for significance using the 2-sided log-rank test. The patient populations analyzed included the intention-to-treat population (all patients who were randomized and who received at least 1 dose of the study medication) and the safety population (all patients who were randomized, who received at least 1 dose of study medication, and who had at least 1 post­randomization safety assessment). Most patients were at intermediate risk for CMV infection (D+/R+ or D−/R+). High-risk candidates (D+/R−) were excluded from data analyses to stratify our patients into a homogenous group of kidney transplant recipients with intermediate risk for CMV infection.

Results

Our intention-to-treat population included 201 candidates who were followed for 12 months. Most of the patients in both groups completed the study as planned with high rate of compliance for follow-up as advised (>95%; Figure 1). All patients were at intermediate risk for CMV infection except 2 in group 1 and 3 in group 2 were at high risk; these patients were excluded from the final analysis, leaving 98 candidates in each group (Figure 1). During the treatment phase, 1 patient from group 1 died due to acute myocardial infarction and 2 patients from group 2 had graft failure (1 due to recurrent oxalosis and 1 due to severe rejection and renal vein thrombosis). After 6 months, 1 patient was lost to follow-up in each group (Figure 1). Among the high-risk patients, only 1 candidate in group 2 was treated for CMV disease at 11 months after transplant; this patient later became seropositive.

The demographic features of the 2 groups were comparable (Table 1; P > .05). The odds ratio of less HLA-A, HLA-B, and HLA-DR mismatches (ie, < 2 mismatches) were significant (> 1) with confidence level of 95% (P < .05; Table 1). More patients were maintained on tacrolimus in group 1, whereas more patients were on cyclosporine in group 2 (P < .05; Table 1). There were no significant differences in delayed graft function and slow graft function between the groups (Table 1).

Table 2 shows that there were a numerically higher number of patients treated for CMV disease in group 2 than in group 1 (P > .05). The number of patients who developed leukopenia attacks, the mean number of leukopenia attacks per patient, the mean dose of G-CSF, the number of patients who needed G-CSF therapy, the mean MMF dose, and the number of patients who required early valganciclovir discontinuation (24 patients in group 1 and 32 patients in group 2) or dose reduction (4 patients in group 2) were significantly higher in group 2 (P < .05). There were an equal number of patients with posttransplant type 2 diabetes mellitus in both groups. Insignificant increase of BK virus-associated nephropathy was seen in group 2, whereas other associated infections were comparable in both groups (P > .05). Only one patient had associated Epstein-Barr virus infection in group 2. During the treatment phase, most patients reported at least 1 mild adverse event other than leukopenia and associated infections (eg, diarrhea, nausea, headache, anemia), which in general occurred at a similar rate between the 2 groups and did not require interruption of the study medication (results not shown). There were no significant differences between the 2 groups regarding graft function as represented by serum creatinine and eGFR (at time of first discharge from hospital after transplant and at 6 and 12 months) (Table 2). Patient and graft outcomes were similar in both groups (Table 2 and Figure 2).

Table 3 shows the details of patients treated for CMV disease without significant differences between the groups regarding demographic data. Numerically higher incidence of CMV infections and leukopenia attacks were reported in group 2 (P > .05). There were no reported cases of resistant CMV infection in our cohort. All CMV-infected patients in group 2 received thymoglobulin induction, with none in group 1. A significant reduction was shown in the total duration of valganciclovir prophylaxis to < 3 months in the high-dose valganciclovir group compared with 6-month duration in the low-dose group and, consequently, early development of CMV infection during the valganciclovir treatment phase (< 6 mo post­transplant) in group 2 (P < .05). We observed a significant delay in the development of CMV disease after transplant in group 1. Three patients had moderate symptoms that required intravenous ganciclovir: 1 patient with chronic diarrhea in each group and 1 with pneumonia in group 1. None of the CMV infections were graded as severe or tissue invasive. Seven CMV-infected patients were labeled as CMV syndrome; all were in group 2 and were treated with oral valganciclovir.

Table 4 shows a numerically higher total number of rejection episodes in group 2, and mixed-type rejection (combined acute cellular rejection and acute antibody-mediated rejection) was significantly higher in group 2.

Discussion

To our knowledge, this is the first randomized head-to-head trial designed to show the differences in efficacy and safety between 2 doses of valganciclovir for universal anti-CMV prophylaxis in an intermediate-risk group of kidney transplant recipients. Our patients were at intermediate risk for CMV infection (D+/R+ or D−/R+), with more leukopenia attacks in the high-dose valganciclovir group. Group 2 required higher doses of supportive G-CSF treatment and significant manipulation of drugs, which resulted in numerically higher CMV infections and rejection episodes.

Demographic features
More than 50% of our kidney transplant recipients were having less HLA-A, HLA-B, and HLA-DR mismatches, which are reported to have a protective effect against CMV infection in solid-organ transplant recipients (Table 1).^29,30 In accordance with other studies, less HLA-DR mismatches had the most protective HLA allele against CMV infection in our cohort, with the highest odds ratio among HLA alleles.^29,30 Schnitzler and associates demonstrated that 5-year graft survival with CMV disease was 75.9% with 1 or 2 HLA-DR matches versus 16.2% with zero HLA-DR matches (P < .001).30 The prevalence of past exposure to CMV is close to 100% in adults in many developing countries.³¹ Most of our kidney transplant recipients and their donors were seropositive, which is comparable with other studies.^10,12,31

Immunosuppression, leukopenia attacks, and rejection episodes
Intensive immunosuppression is one of the main precipitating factors for CMV disease.5,6 Half of our patients received thymoglobulin (Table 1), which has a severe bone marrow suppressive effect.^27,28 Because thymoglobulin treatment was equal in both groups, we looked for other causes for the high incidence of leukopenia in group 2. Tacrolimus can cause more leukopenia than cyclosporine.^27,28 However, fewer patients had received tacrolimus in group 2 (P < .05), which had more leukopenia attacks. In addition, the greater numbers of patients in group 2 with cyclosporine treatment may have caused less exposure to mycophenolic acid than the tacrolimus-MMF combination in group 1. Therefore, the higher number of leukopenia attacks in group 2 are likely related to the high-dose effect of valganciclovir than tacrolimus or MMF.³²

The prevalence of significant leukopenia (white blood count < 3.0/L) is reported as occurring in up to 58% of kidney transplant recipients.^33,34 Multiple immunosuppressive drugs and other medications are encountered in causing significant leukopenia in these patients.^32-35 Posttransplant leukopenia increases the risk of infectious diseases and subsequently more use of bone marrow suppressive antimicrobial agents.^32-35 Mycophenolate mofetil is one of the mainstay immunosuppressive drugs during the past 2 decades.^34-37 The leukopenia attacks were managed by significant MMF dose reduction (P < .05; Table 2). Mycophenolate mofetil dose reduction and less exposure to mycophenolic acid due to cyclosporine-MMF combination could be the cause for the numerically higher rejection episodes in the high-dose valganciclovir group compared with group 1 (Tables 2 and 4).³² The numerically higher numbers of patients with BK virus-associated nephropathy and CMV infection in group 2, requiring reduction of immunosuppressive agents, can be additional factors to precipitate graft rejection (Tables 2 and 4).³⁸ Mixed-type rejections (acute cellular rejection+ antibody-mediated rejection) were significantly higher in group 2, requiring intensive immuno­suppressive treatment, and could be an additional risk factor to develop higher incidence of CMV disease in this group.

A more significant amount of G-CSF was required to treat the leukopenia attacks in group 2, demonstrating the severity of these attacks in this group compared with group 1. Moreover, these attacks were treated by reduction or stopping of valganciclovir, which interrupted the prophylactic effect of the drug against CMV disease in group 2 significantly to < 3 months (Table 2). Less leukopenia attacks in group 1 led to a prolonged and steadier prophylactic drug effect and consequently less CMV infections.

Cytomegalovirus disease
Internationally, the incidence of posttransplant CMV infection has been reduced from about 60% in the absence of prophylaxis to 5% to 30% with anti-CMV prophylaxis, depending on the prophylactic regimen and CMV serostatus of the donor and the recipient.^{1,6,7,19,20,23} Despite high incidence of thymoglobulin use in our cohort, the incidence of CMV disease was low (5%) without significant differences between the groups. This could be related to less incidence of HLA-A, HLA-B, and HLA-DR mismatches in our patients, the regular screening program applied to them, and the use of universal valganciclovir prophylaxis (Table 1).^11,29,30,39 The number of patients treated for CMV disease was numerically higher in group 2 despite similarity in HLA-B and HLA-DR mismatch, risk population for CMV infection, and intensity of immunosuppression received in both groups (Tables 1 and 3). The main difference was in the valganciclovir prophylactic dose and duration, with the effect of having more leukopenia attacks in group 2 (P < .05) and subsequently interrupted valganciclovir prophylactic course (<3 mo; P < .05), which led to early development of CMV disease in group 2 during the treatment phase (P < .05). Longer duration of a steady course of low-dose valganciclovir for 6 months resulted in the occurrence of numerically less CMV infections, supporting the use of this prophylactic regimen in intermediate-risk kidney transplant recipients. A detailed previous phar­macokinetic study of low-dose valganciclovir (450 mg daily) suggested that it provides ample drug exposure for effective CMV prophylaxis in kidney transplant recipients.⁴⁰ Similar to the philosophy behind the preemptive strategy, the low-level viremia that possibly occurs with low-dose valganciclovir therapy may facilitate CMV-specific immune reconstitution and thus mitigate the risk of CMV disease.⁴¹ Gabardi and associates also concentrated on intermediate-risk patients (>80%) and concluded that valganciclovir administered at 450 mg/d for 6 months was effective and relatively safe for prophylaxis of CMV disease in kidney transplant recipients.⁴² Emergence of CMV resistance is a major concern with low-dose valganciclovir, especially for high-risk patients.¹⁸ Our study included intermediate-risk patients who had lower incidence of CMV infections and did not report any CMV resistance. Recent studies have highlighted a benefit of long-term high-dose valganciclovir prophylaxis (6 mo) in terms of CMV disease occurrence and to avoid breakthrough infections among D+/R− patients; however, recommendations regarding treatment of intermediate-risk kidney transplant recipients are still unclear.^43,44 Our study demonstrated a numerically lower incidence of CMV infections with steady 6-month low-dose valgan­ciclovir among an intermediate-risk group with better safety profile compared with the high-dose regimen.

Associated infections
Numerically, more cases of BK virus nephropathy were reported in group 2 (Table 2). Similar to our findings, CMV and BK virus infections can coexist.38 Simultaneously, CMV infection may have accelerated the process of rejection and reactivation of BKV shown in group 2.³⁸

Study limitations
Adequate understanding of the pharmacokinetics and drug manipulations during the treatment phase was affected by the lack of MMF and valganciclovir drug level monitoring. The study also did not collect detailed data of the cost effectiveness. Our results suggest that low-dose valganciclovir prophylaxis may have the same effect as a high dose, with favorable economic benefits as concluded from other studies.⁴⁵ A formal cost-effective analysis of the data from this study is currently in progress.

Our study highlighted the risk factors for development of CMV disease regarding the demo­graphics, the intensity of immunosuppression, drug manipulation of antimetabolites, valganciclovir for drug-induced leukopenia, and details of G-CSF doses used. Our data contribute to a better under­standing of the clinical consequences of high-dose valganciclovir and drug-related adverse effects. Because most kidney transplant recipients are at intermediate risk for CMV infections, further studies addressing pharmacokinetics, duration of low-dose valganciclovir prophylaxis, and its effect on longer-term CMV infections in this group of patients are warranted.

Conclusions

After 1 year, a low-dose valganciclovir regimen for 6 months for prevention of CMV disease after renal transplant was as effective as the high-dose regimen with a better safety profile (less leukopenia attacks and less manipulation of chemoprophylactic and immunosuppressive drugs).

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