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VolumeIIII••Number Number12••January-April May-August 2008 Volume ISSN: 1887-455X

05.08-CEL-RE07

12.07-CEL-A10

www.trendsintransplantation.com

Ver ficha técnica en página 101

Pharmacokinetics and Pharmacodynamics Chronic Allograft Nephropathy (CAN) – An Update of Mycophenolic Acid: Different Formulations Thomas Afzali and David Goldsmith in StableOates, RenalBehdad Transplant Patients 3 Dario Cattaneo 51 Alemtuzumab as Induction Therapy in Renal Cardiovascular Risk in Renal Transplantation Transplantation Bengt C. Fellström, Halvard Holdaas and Alan G. Jardine Menna R. Clatworthy and Christopher J.E. Watson 62 12 Quality of Life as an Indicator of the Effectiveness of Simultaneous Pancreas-Kidney Transplantation Small Bowel Successful Pilar Isla Pera,Transplantation: Joaquin MonchoHow Vasallo, Alberto Torras Can It Be? Rabasa and María José Ricart Brulles 69 Kohler, Johann Pratschke, Peter Neuhaus and Sven

Andreas Pascher Adult Liver Transplantation in HIV-1 Infected Patients 24 Fernando Agüero, Montserrat Laguno, Montserrat Tuset, Carlos Cervera, Asunción Moreno, Juan-Carlos García-Valdecasas, Rimola, José M. Miró, Understanding the Antonio Molecular Mechanisms Involved and the Hospital Clinic OLT in HIV Working Group in Indirect Effects of Cytomegalovirus 78 Cecilia Söderberg-Nauclér, Mensur Dzabic Optimal and AfsarLength Rahbarof Valganciclovir Prophylaxis after Solid Organ Transplantation 32 Albert J. Eid, Carlos V. Paya and Raymund R. Razonable 92

Mucho por vivir

Frente al CMV... Valcyte. El paso más firme hacia el futuro. Prevención y tratamiento del CMV.

12.07-VAL-A07

C M V Ver ficha técnica en página 103

Roche Farma, S.A. C/ Eucalipto, 33 28016 Madrid Tel.: 91 324 81 00 Fax: 91 744 10 27 www.roche.es

Volume II • Number 2 • May-August 2008 ISSN: 1887-455X www.trendsintransplantation.com

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Copyright © 2008 by P. Permanyer Mallorca, 310 - 08037 Barcelona Tel.: +34 93 207 59 20    Fax: +34 93 457 66 42 E-mail: [email protected] ISSN: 1139-6121 • Dep. Leg. B-12.128/2007 Presentation for valid support registration ner. 0359E/343/2008 - 11/01/2008 Generalitat de Cataluña, Health Department (Gran Vía), Barcelona, Spain Ref.: 1301AM072 Printed on acid-free paper Printed by Comgrafic This paper meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of paper) All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronically, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Timely topics in Trends in Transplantation research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by Trends in Transplantation Editors and Publishers. No responsibility is assumed by Trends in Transplantation Publisher for any injury and/or damage to persons or property as result of product liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends that independent verification of diagnoses and drug dosages should be made.

Trends in Transplant. 2008;2:51-61

Dario Cattaneo: Pharmacokinetics of MPA formulations

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid: Different Formulations in Stable Renal Transplant Patients Dario Cattaneo Center for Research on Organ Transplantation “Chiara Cucchi de Alessandri and Gilberto Crespi”, Mario Negri Institute for Pharmacological Research, Bergamo, Italy

Abstract Mycophenolic acid has gained widespread acceptance as the antimetabolite of choice in most of the immunosuppressive regimens, thanks to its selective action versus T and B cells. This drug is characterized by a narrow therapeutic index and a well-documented relationship between efficacy (in terms of acute rejection episodes) and exposure to mycophenolic acid (as AUC and C0). For these reasons, in the past years there has been an increased interest in the utility of monitoring mycophenolic acid concentration to optimize drug dosing. Currently, two prodrugs of mycophenolic acid are available, namely mycophenolate mofetil and the enteric-coated formulation of mycophenolate sodium. Both formulations provide comparable distribution, metabolism and excretion of mycophenolic acid. However, important differences in drug absorption have been reported. Some of them were expected, being related to the enteric-coating film of mycophenolate sodium that delayed the absorption of mycophenolic acid, resulting in higher Tmax values compared to those measured with mycophenolate mofetil. Nevertheless, a number of studies reported that the novel entericcoated formulation of mycophenolic acid produced aberrant and extremely variable pharmacokinetic profiles, characterized by multiple peaks of mycophenolic acid concentrations and high basal drug concentrations. According to these preliminary data, mycophenolate sodium and mycophenolate mofetil cannot be formally considered as bioequivalent. Moreover, the growing body of literature on the importance of therapeutic drug monitoring of mycophenolic acid poses concerns also on the “clinical equivalence” between the two formulations. It is, indeed, very unlikely that all the monitoring strategies applied in the past years for mycophenolate mofetil could be applied in patients given mycophenolate sodium, due to the erratic and extremely variable absorption of the novel formulation. As an additional limitation, no data are available yet on the factors that could potentially affect

Correspondence to: Dario Cattaneo Unit of Pharmacology and Pharmacogenetics Mario Negri Institute for Pharmacological Research Via Camozzi, 3 24020 Ranica (BG), Italy E-mail: [email protected]

51

Trends in Transplantation 2008;2

the pharmacokinetics of mycophenolic acid released from mycophenolate sodium. Certainly, this information cannot be simply extrapolated from previous observations in patients given mycophenolate mofetil. As a support of this, it has been recently shown that the two mycophenolic acid formulations may be differently affected by concomitant therapies and/or comorbid conditions. As far as pharmacodynamic comparisons between mycophenolate mofetil and mycophenolate sodium, available data are too scanty to reach definitive conclusions, so that, at the present time, the monitoring of inosine monophosphate dehydrogenase activity (the pharmacologic target of mycophenolic acid) cannot be considered as a viable alternative to pharmacokinetic-based approaches. In conclusion, evidences collected in more than 10 years of clinical use of mycophenolic acid have documented that this drug has important pharmacological properties that can be optimized by tailoring the best dosage for each patient according to periodical evaluations of the plasma levels. Nevertheless, this monitoring approach can, at the present time, be reliably applied only in patients on mycophenolate mofetil, but not in those treated with mycophenolate sodium. (Trends in Transplant. 2008;2:51-61) Corresponding author: Dario Cattaneo, [email protected]

Key words Mycophenolic acid. Pharmacokinetics. Pharmacodynamics. Organ transplantation. Pharmaceutical formulations. Bioequivalence.

Introduction Since the introduction of cyclosporine to organ transplantation in the early 1980s, therapeutic drug monitoring has become an integral part of immunosuppressive agents1. These molecules are characterized by narrow therapeutic indexes, and therefore, small variations in the pharmacokinetic profiles may induce an inadequate level of immunosuppression, resulting either in increased risk to reject the graft, or magnification of drug-related adverse events1. These concepts apply to mycophenolic acid (MPA), an antimetabolite that, thanks to its selective action versus immunocompetent cells, has replaced azathioprine as part of the maintenance immunosuppressive therapies in most transplant centers. In fact, at variance with azathioprine that acts as a non-selective antimetabolite, MPA is a potent selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), a key enzyme involved in the de novo synthesis 52

of guanine nucleotides, which are critical for the proliferation of T and B lymphocytes2, whereas other cell types (i.e. erythrocytes) can utilize alternative pathways (the salvage pathway). Currently, two mycophenolate compounds are available, namely mycophenolate mofetil (MMF) and the enteric-coated mycophenolate sodium (EC-MPS). Both formulations act as prodrugs and are, therefore, characterized by the same mechanism of action. There are, however, some important differences in the pharmacokinetic properties that will be the topic of the present review.

Mycophenolate mofetil Mycophenolate mofetil is the 2,4-morpholinoethyl ester of MPA. It is marketed for oral administration in capsules (250 mg), tablets (500 mg), or as powder for suspension. In some countries, MMF is available also as intravenous formulation as MMF hydrochloride (524 mg corresponding to 500 mg of MMF).

Dario Cattaneo: Pharmacokinetics of MPA formulations

Following oral administration, MMF is absorbed rapidly and completely from the gastrointestinal tract and undergoes extensive presystemic de-esterification to MPA, the active moiety. In the whole blood, MPA is found exclusively in the plasma fraction, mainly bound to albumin, with a binding > 95%. In vitro and in vivo studies have consistently shown that only free MPA (the fraction unbounded to albumin) is capable of inhibiting IMPDH2. Mycophenolic acid is metabolized via glucuronidation in the gastrointestinal tract, liver and, to a lesser extent, in the kidney. Mycophenolic acid glucuronide (MPAG), the main metabolite, is a phenolic glucuronide of MPA with no pharmacologic activity. At least two other minor metabolites have been recently identified: the 7-0-glucoside and the acyl MPAG. More than 90% of the drug is excreted into the urine as MPAG via active tubular secretion. Following MMF administration, MPA Tmax usually occurs 1-2 hours post-dose, with the appearance of a secondary peak at around 4-12 hours, attributed to enterohepatic recirculation of MPAG excreted into the bile, which is deconjugated back to MPA and reabsorbed in the colon through the action of glucuronidase shed by gastrointestinal tract bacteria. The mean elimination half-life of MPA ranges from 9-17 hours 2.

Mycophenolate sodium Enteric-coated mycophenolate sodium (EC-MPS), the sodium salt of MPA, is available for oral use as a delayed-release tablet containing either 180 or 360 mg of MPA. This formulation was designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until reaching the small intestine3. A study investigating the dissolution of EC-MPS tablets has shown that MPA is maximally released at a pH of 6.0-6.8 after 120 minutes, with results at pH 5.0 showing a slower and less complete release of MPA4. These data confirm that MPA is released from EC-MPS in the more alkaline environment of the small intestine, whereas the gastric absorption, if any, is negligible.

The processes of distribution, metabolism and excretion of MPA from EC-MPS are compar­ able to those reported for MMF2. There are, however, some peculiar characteristics in the drug absorption that are dictated by the nature of the formulation. In particular, studies in stable kidney transplant recipients treated with single doses of EC-MPS have documented MPA Tmax ranging from 120-180 minutes, and variable half-life values varying between 5-8 hours5-7.

Pharmacokinetic comparison between the two mycophenolic acid-releasing formulations Two randomized, multicenter, clinical trials have shown that both in the de novo and in maintenance renal transplant recipients, the two MPA formulations were comparable in terms of efficacy and safety when given on fixed-dose regimens8,9. These evidences have led the transplant community to consider MMF and EC-MPS as “clinically bioequivalent”. Accordingly, in clinical practice, 1,000 mg of MMF are considered equivalent to 720 mg of EC-MPS. Nevertheless, it should be stressed that “clinical equivalence” does not fully fit with the concept of “chemical equivalence”. In fact, 1,000 mg of MMF delivers 2.31 moles of MPA, whereas 720 mg of EC-MPS corresponds to 2.24 moles of MPA. Although this difference could be considered minimal, it argues against the widespread misconception of bioequivalence between the two MPA formulations. Indeed, according to international consensus guidelines, two drugs can be considered as bioequivalent when they contain the same molecular entity, share an exactly equal qualitative/quantitative composition and identical pharmaceutical formulation. Classically, demonstration of bioequivalence between two formulations requires spe­ cific pharmacokinetic evaluations, showing that the 90% confidence intervals of the relative main pharmacokinetic parameters (usually mean AUC and Cmax) of the test to reference formulation would be within 80-125%. Looking in the literature, there are only few studies published in peer-review journals that have formally com53

Trends in Transplantation 2008;2

pared the pharmacokinetics of MPA from ECMPS with that released by MMF (as summarized in table 1). Overall, most of these studies have shown that limiting only to mean MPA AUC values, the two formulations could be considered as bioequivalent. This trend, however, was not confirmed when comparing the other main pharmacokinetic parameters (i.e. Cmax, C0, Tmax). In our clinical research center, we have recently conducted a comparative study involving kidney transplant recipients treated with ECMPS or MMF for 24 months after surgery13, with full MPA pharmacokinetic evaluations performed in both groups every six months. During all evaluations, aberrant and variable pharmacokinetic curves were found in patients who were given the novel enteric-coated formulation of MPA, whereas those on MMF had regular MPA kinetic profiles. Moreover, patients on EC-MPS presented extremely high C0 concentrations, multiple peak of MPA, and Tmax values ranging from 0-480 minutes, while those on MMF showed a sharp peak of maximum drug concentration always within 1-2 hours after drug intake (Figs. 1 and 2). To take into account potential bias related to patient selection, we decided to switch at month 24 after transplantation all kidney transplant recipients who were given EC-MPS to MMF. In this way, we found that the conversion resulted in a significant reduction in the MPA C0 levels, with values comparable to those measured in patients who were given MMF throughout the study period. Notably, in patients who were shifted from EC-MPS to MMF, the atypical daily MPA profile did normalize, being associated with less variability in the main pharmacokinetics parameters (Fig. 1). These findings further indicate that the high variability in MPA absorption observed with EC-MPS was just linked to the novel formulation of MPA and not to potential bias in patient selection.

The emerging role of therapeutic drug monitoring Both MMF and EC-MPS are usually administered at fixed daily oral dosages and thera54

peutic drug monitoring is not routinely performed. Nevertheless, recent evidence sug­gests that MPA pharmacokinetic monitoring could be advisable at least in patients treated with MMF (no data are available on EC-MPS). Accordingly, concentration-contro­lled approaches can be helpful to limit intrapatient variability of daily MPA exposure and to improve the clinical outcome of organ transplant recipients16. The first seminal study on this topic was published by van Gelder, et al. 17, in which 150 adult recipients of a primary or secondary cadaver kidney graft were randomly allocated to receive MMF treatment aimed at three predefined target MPA AUC values. Logistic regression analysis showed a highly statistically significant inverse relationship between MPA AUC (or MPA C0) and the occurrence of a biopsy proven rejection, whereas this was not the case when using mean MMF dose. Subsequently, others have demonstrated important associations between MPA pharmacokinetics and graft function after kidney trans­plantation18 or MMF-related adverse events19. Of particular relevance are the recent results of the French APOMYGRE trial20. In this 12-month study, 137 renal allograft recipients receiving basiliximab, cyclosporine, MMF, and corticosteroids were randomized to receive either concentration-controlled doses or fixed-dose MMF. A novel Bayesian estimator of MPA AUC ba­sed on three-point sampling was used to individualize MMF doses. The primary endpoint was treatment failure (death, graft loss, acute rejection, and MMF discontinuation). The stu­dy showed that at month 12, the concentration-controlled group had significantly fewer treatment failures (48 vs. 29%) and acute rejection episodes (8 vs. 25%) compared to patients kept on fixed MMF dose, confirming the clinical relevance of therapeutic MPA mo­nitoring. Taken together, all these evidences ha­ve led to the definition of provisional target therapeutic ranges for MPA AUC and trough concentrations to be applied in clinical practice. When combined with cyclosporin A (CsA), the recommended target ranges are 1-3.5 mg/l and 30-

Cyclosporine Steroids?

Cyclosporine Steroids?

Tacrolimus

Cyclosporine Steroids?

Cyclosporine No steroids

Cyclosporine Steroids

Cyclosporine Steroids

24 kidney transplant recipients

32 heart transplant recipients

21 kidney transplant recipients

18 kidney transplant recipients

32 kidney transplant recipients

82 kidney transplant recipients

20 kidney transplant recipients

Parallel groups

Meta-analysis including 3 studies with crossover design

Parallel groups for 24 months, then conversion from EC-MPS to MMF

Parallel groups

Conversion from MMF to EC-MPS

Parallel groups

Cross-over, single doses of EC-MPS or MMF

Study design

EC-MPS delivered bioequivalent mean MPA exposure (as AUC) compared with MMF

Bioequivalence between EC-MPS and MMF was found pooling the 3 trials together

Patients on EC-MPS had aberrant and variable MPA pharmacokinetic profiles characterized by high C0 values and multiple peaks

Equimolar doses of EC-MPS and MMF produce equivalent MPA exposure (as AUC)

MMF and EC-MPS are associated with similar MPA exposure (as AUC)

EC-MPS and MMF provided comparable mean MPA AUC values

EC-MPS delivered bioequivalent mean MPA exposure (as AUC) compared with MMF

Main results

LSS: limited sampling strategies; MPA: mycophenolic acid; MMF: mycophenolate mofetil; EC-MPS: enteric-coated mycophenolate sodium.

Therapies

Patients

Data on basal MPA values were not given Too much outlayers Some kinetic profiles were estimated by LLS Bioequivalence was not confirmed by Cmax values

Data on basal MPA values were not given Too much outlayers Some kinetic profiles were estimated by LLS

Use of low-dose protocols Lack of cross-over evaluations No data from patients on tacrolimus

MPA levels were measured by EMIT assay Some but not all patients were on steroids Some kinetic profiles were estimated by LLS Bioequivalence was not confirmed by Cmax values Patients with MPA C0 > 10 mg/l were excluded

Patients were at different time after transplantation Some but not all patients were on steroids Bioequivalence was not confirmed by Cmax values

Pharmacokinetic profiles were not presented Basal MPA values were not given

Patients were not on steady-state conditions Bioequivalence was not confirmed by Cmax values

Comments

Johnston, et al.14

Johnston, et al.14

Cattaneo, et al.13

Budde, et al.12

Budde, et al.11

Yonan, et al.10

Arns, et al.4

References

Table 1. Summary of the studies that have compared the pharmacokinetics of mycophenolic acid from enteric-coated mycophenolate sodium and mycophenolate mofetil

Dario Cattaneo: Pharmacokinetics of MPA formulations

55

Trends in Transplantation 2008;2

50 Month 24

Month 6

Month 30

40 30

EC-MPS

EC-MPS

Conversion to MMF

20 10 0 0 50

120 240 360 480 600 720

0

120 240 360 480 600 720

0

Month 24

Month 6

120 240 360 480 600 720

Month 30

40 30

MMF

MMF

MMF

20 10 0 0

120 240 360 480 600 720 Time (min)

0

120 240 360 480 600 720 Time (min)

0

120 240 360 480 600 720 Time (min)

Figure 1. Daily MPA pharmacokinetic profiles from kidney transplant recipients given EC-MPS or MMF as part of their maintenance immunosuppressive regimens. At the end of month 24 posttransplantation all patients on EC-MPS were shifted to MMF13. MPA: mycophenolic acid; MMF: mycophenolate mofetil; EC-MPS: enteric-coated mycophenolate sodium.

60 mg·h/l for trough concentration and AUC, respectively. For the combination with tacrolimus, the suggested MPA target ranges are 1.9-4.0 mg/l for trough and 30-60 mg·h/l for AUC16,21. Nevertheless, it is of paramount importance to underline the fact that these ranges derive from studies involving patients treated with MMF, and therefore can be applied only with this formulation of MPA. At the present time, it is thus not possible to know whether the proposed therapeutic windows could apply also in patients on EC-MPS, simply because no therapeutic drug monitoring stu­dies are available with the novel MPA formulation. On the other hand, indirect evidences are available suggesting that, for sure, pa­tients given EC-MPS will not benefit from the mo­nitoring of MPA C0 concentrations as a gui­de to optimize drug therapy. Indeed, different stu­dies have reported unexpectedly high MPA C0 values in pa56

tients chronically given EC-MPS that, in some instances, exceeded 40 mg/l 13,22, whereas basal MPA concentrations measured in patients on MMF usually ranged from 1-8 mg/l. At the same time, others have documented comparable mean MPA Cmin values between the two formulations10,11. It should be pointed out, however, that this discrepancy is only apparent, being mainly affected by the erroneous interchangeability of the terms C0 and Cmin. For this purpose, it must be remembered that the term “C0” (or trough, basal) refers to the concentration of a given drug measured (in blood, plasma, or serum) just before the next medication dosage is given, whereas Cmin represents the lowest concentration of a drug reached in the body between dosages. According to these definitions, the two parameters indicate different concepts, and therefore may not necessary coincide. As

420

105

30

360

90

25

300

20 15 10 5

MPA AUC (mg*h/l)

35

MPA Tmax(min)

MPA C0 (mg/l/eq MPA)

Dario Cattaneo: Pharmacokinetics of MPA formulations

240 180 120

MMF

45 30

0

0 EC-MPS

60

15

60

0

75

EC-MPS

MMF

EC-MPS

MMF

Figure 2. Box-plot showing the distribution of the main MPA pharmacokinetic parameters (C0, Tmax and AUC0-12) in kidney transplant recipients given EC-MPS or MMF13. MPA: mycophenolic acid; MMF: mycophenolate mofetil; EC-MPS: enteric-coated mycophenolate sodium.

an example, in our study we found that EC-MPS presented comparable Cmin values, but significantly different C0 drug concentrations (Fig. 3). When using the right definition of basal drug concentrations, all the published studies consistently agreed that the novel enteric-coated formulation provided significantly higher MPA C0 values than those measured in patients on MMF12,13,22,23. These differences may be relevant not only for pure pharmacokinetic disquisitions, but, eventually, also from a clinical perspective. In fact, it must be considered that the high concentrations of MPA C0 observed in patients given EC-MPS do not parallel with increased AUC values13, rendering the assessment of the former parameter, which is routinely performed in patients on MMF, totally useless and potentially harmful if applied in patients on EC-MPS because it might lead to erroneous dose adjustments with the potential risk of drug underdosing.

The issue of drug-to-drug interactions Some important drug-to-drug interactions have been reported for MMF2. One of the most frequently observed interactions in organ transplant recipients involves the concomitant administration of cyclosporine and MMF. In particular,

it has been demonstrated that cyclosporine inhibits biliary excretion of MPAG by multidrug resistance associated pro­tein 2 (MRP2) transporter15. This leads to impaired excretion of MPAG in the bile and reduced enterohepatic recirculation of MPAG, blunting the secondary peak of MPA normally seen when MMF was given in combination either with tacrolimus or sirolimus15,24. Nevertheless, it should be considered that findings on drug-to-drug interactions involving MMF cannot be automatically extrapolated also for EC-MPS. As a partial support of this statement, a randomized, calcineurin inhibitor crossover study has demonstrated that, at variance with previous observations with MMF15, the switch between cyclosporine to tacrolimus (and vice versa) has only minor effects on MPA pharmacokinetics in stable renal transplant patients receiving EC-MPS5.

Different effects of mycophenolic acid formulations on the pharmacokinetics of calcineurin inhibitors The calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the backbone of immunosuppression for most organ transplant recipients. Both drugs are characterized by narrow 57

Trends in Transplantation 2008;2

12

MPA connc. (mg/l)

10

*

8 6 4 2 0 EC-MPS

MMF C0

EC-MPS

MMF

Cmin

Figure 3. Differences in the C0 and Cmin values observed in kidney transplant patients on EC-MPS or MMF13. MPA: mycophenolic acid; MMF: mycophenolate mofetil; EC-MPS: enteric-coated mycophenolate sodium.

therapeutic indexes, irregular absorption, and high intrapatient variability in the daily drug exposure. Moreover, many investigations have consistently documented signi­ficant associations between the pharmacokinetics of CNI and the outcome of patients after transplantation, where low concentrations were associated with an increased risk for rejection, and high levels correlated with drug-related to­xi­city (reviewed25). Accordingly, therapeutic drug monitoring is routinely adopted in all transplant centers as a guide to tailor the best CNI dosage for each patient. For these reasons, it is likely that any factor able to significantly alter the daily exposure of cyclosporine or tacrolimus might have potential clinical implications. In this regard, a comparative study involving kidney transplant recipients given cyclosporine in combination either with EC-MPS or MMF has shown that the MPA formulations significantly affected the pharmacokinetics of the CNI26. During all the kinetic evaluations, patients on EC-MPS had a shift to the right in the cyclosporine peak concentration as compared to that 58

observed in patients given MMF, an effect associated with significant differences in Tmax values. In particular, the authors found that the majority of patients on EC-MPS had cyclosporine peaking at two hours post-dosing, whereas most of patients on MMF had Cmax at one hour. To assess whether these fin­dings should be ascribed to EC-MPS or to MMF, we compared the pharmacokinetics of cy­closporine from these patients with those mea­sured in patients given the CNI in combina­tion with azathioprine27. As shown in figure 4, the pharmacokinetics of cyclosporine measu­red in patients given MMF or azathioprine were fully overlapped and differed significantly from the kinetic profiles observed in patients on EC-MPS, suggesting that the shift in the cyclosporine Tmax was clearly related to the novel formulation of MPA. These findings would imply that cyclosporine C2 values, recently proposed as a novel single-point monitoring strategy, may assume a different meaning according to the MPA formulation given concomitantly. Notably, two independent studies have recently shown that simultaneous administration

Dario Cattaneo: Pharmacokinetics of MPA formulations

1000

EC-MPS (n = 12) *

MMF (n = 20) AZA (n = 50)

CsA conc. (ng/ml)

800

600 * °

400

°

*

200

°

°

10

12

*p < 0.01 vs. MMF and AZA °p < 0.05 vs. MMF and AZA

0 0

2

4

6

8

Time (h)

Figure 4. Distribution in the daily CsA pharmacokinetic profiles in kidney transplant recipients given EC-MPS, MMF or azathioprine (adapted from Refs. 26,27). MMF: mycophenolate mofetil; EC-MPS: enteric-coated mycophenolate sodium; CsA: cyclosporin A; AZA: azathioprine.

of EC-MPS induced significant alterations also in the pharmacokinetics of tacrolimus as compared with those observed with MMF23,28. Taken together, these results suggest that the novel formulation of MPA, probably due to its entericcoated film, can significantly alter the absorption of both CNI. The clinical implications of these findings remain, however, to be established.

Pharmacodynamic monitoring of mycophenolic acid Pharmacodynamic monitoring by measurement of IMPDH activity is a novel approach to individualize MPA therapy as it may better reflect biological response to the drug2. Nevertheless, the widespread application of this approach was limited by the complex methodology of the assay, which was technically de­manding. These shortcomings have been overcome by the development of validated high-performance liquid chromatography (HPLC) methods able to estimate enzyme activity by measuring the rate

of conversion of inosine monophosphate to xanthine monophosphate in PBMC, a reaction that is selectively catalyzed by IMPDH29. In the past few years, this assay has been applied in organ transplant recipients given MMF as part of their maintenance immunosuppressive regimens (reviewed29) with pro­mising results. Remarkably, Glander, et al. have found that pretransplant IMPDH activity significantly correlated with clinical outcome after renal transplantation, both in terms of acute rejection episodes and complications of MMF therapy30. To date, only two studies have focused on the pharmacodynamics of MPA in patients given EC-MPS11,12. Both studies showed that maintenance renal transplant patients given tacrolimus or cyclosporine and converted from MMF to EC-MPS showed that the two MPA formulations provided comparable mean inhibition of IMPDH activity (approximately 85%). It should be underlined, however, that these studies reported a very large between-subject variability 59

Trends in Transplantation 2008;2

in the IMPDH activity, a condition that might have potentially biased the conclusions. Moreover, as an additional drawback, only a very few patients were enrolled in the present investigations. Due to the high variability in the results observed with both MPA formulations and the lack of validated ad hoc prospective clinical trials, the monitoring of IMPDH activity cannot be considered at the present time as a viable alternative to pharmacokinetic-based approaches.

Conclusions Available data suggest that from a che­ mical-pharmacokinetic point of view, EC-MPS and MMF cannot be formally considered bioequivalent. Moreover, the growing body of literature on the importance of therapeutic drug monitoring of MPA poses concerns also on the “clinical equivalence” between the two formulations. It is, indeed, very unlikely that all the monitoring strategies applied in the past years for MMF, based on the measurement of basal MPA concentrations or on the prediction of the daily drug exposure (as AUC), could be applied in patients given EC-MPS due to the erratic and extremely variable absorption of the novel formulation. As an additional restraint, no detailed data are available on the factors that could potentially affect the pharmacokinetics of MPA released from EC-MPS. At this stage this information cannot be simply extrapolated from previous observations in patients given MMF. In fact, preliminary evidences have shown that concomitant therapies may have a diverse influence on the two formulations of MPA4,15. Similarly, EC-MPS and MMF may be differently affected by coexistent pathologies, as has recently shown with diabetes, where the disease significantly altered the pharmacokinetics of MPA in patients given MMF but not in those on EC-MPS31,32. In conclusion, evidences collected during more than 10 years of clinical use of MPA have documented that this drug has important phar60

macological properties that might eventually go beyond the immunosuppressive activity33. The use of this drug can be optimized by tailoring the best dosage for each patient according to periodical evaluations of the plasma levels. Nevertheless, this monitoring approach can only, at the present time, be reliably applied in patients on MMF but not in those treated with EC-MPS.

Acknowledgements The Author is undoubtedly grateful to the Foundation ART for Research on Trans­plan­ta­ tion Onlus for the continuous support.

References

















1. Oellerich M, Armstrong VW. The role of therapeutic drug monitoring in individualizing immunosuppressive drug therapy: recent developments. Ther Drug Monit. 2006;28:720-5. 2. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmaco­dynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46:13-58. **A very comprehensive and updated re­ view on the pharmacology of my­co­phenolic acid. 3. Budde K, Glander P, Diekmann F, et al. Review of the immunosuppressant enteric-coated mycophenolate sodium. Expert Opin Pharmacother. 2004;5:1333-45. 4. Arns W, Breuer S, Choudhury S, et al. Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure com­pared with mycophenolate mofetil. Clin Transplant. 2005;19:199-206. 5. Kaplan B, Meier-Kriesche HU, Minnick P, et al. Randomized calcineurin inhibitor cross over study to measure the pharmacokinetics of coadministered enteric-coated mycophenolate sodium. Clin Transplant. 2005;19:551-8. 6. Ettenger R, Bartosh S, Choi L, et al. Pharmacokinetics of en­tericcoated mycophenolate sodium in stable pediatric renal transplant recipients. Pediatr Transplant. 2005;9:780-7. 7. Perry TW, Christians U, Trotter JF, et al. Pharmacokinetics of entericcoated mycophenolate sodium in stable liver trans­plant recipients. Clin Transplant. 2007;21:413-6. 8. Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated my­cophenolate sodium is therapeutically equivalent to MMF in de novo renal transplant patients. Am J Transplant. 2004;4:231-6. * The first trial comparing the therapeutic effects of MPA formulations. 9. Budde K, Curtis J, Knoll G, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant. 2004;4:237-43. 10. Hummel M, Yonan N, Ross H, et al. Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with MMF in de novo heart transplant recipients. Clin Transplant. 2007;21:18-23. 11. Budde K, Glander P, Krämer BK, et al. Conversion from MMF to enteric-coated mycophenolate sodium in maintenance renal transplant recipients receiving tacrolimus: clinical, pharmacokinetic, and pharmacodynamic outcomes. Transplantation. 2007;83:417-24. 12. Budde K, Bauer S, Hambach P, et al. Pharmacokinetic and pharmacodynamic comparison of enteric-coated mycophenolate sodium and MMF in maintenance renal transplant pa­tients. Am J Transplant. 2007;7:888-98. 13. Cattaneo D, Cortinovis M, Baldelli S, et al. Pharmacokinetics of mycophenolate sodium and comparison with the mofetil formulation in stable kidney transplant recipients. Clin J Am Soc Nephrol. 2007; 2:1147-55. 14. Johnston A, He X, Holt DW. Bioequivalence of enteric-coated mycophenolate sodium and MMF: a meta-analysis of three studies in stable renal transplant recipients. Transplantation. 2006;82:1413-8. 15. Hesselink DA, van Hest RM, Mathot RA, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant. 2005;5:987-92. * An experimental study providing the mechanism responsible for the interaction between CsA and MMF.

Dario Cattaneo: Pharmacokinetics of MPA formulations 16. Jeong H, Kaplan B. Therapeutic monitoring of mycophenolate mofetil. Clin J Am Soc Nephrol. 2007;2:184-91. 17. van Gelder T, Hilbrands LB, Vanrenterghem Y, et al. A randomized double-blind, multicenter plasma concentration con­trolled study of the safety and efficacy of oral MMF for the prevention of acute rejection after kidney transplantation. Transplantation. 1999;68:261-6. 18. Cattaneo D, Gaspari F, Ferrari S, et al. Pharmacokinetics help optimizing MMF dosing in kidney transplant patients. Clin Transplant. 2001;15:402-9. 19. van Besouw NM, van der Mast BJ, Smak Gregoor PJ, et al. Effect of MMF on erythropoiesis in stable renal transplant patients is correlated with mycophenolic acid trough levels. Nephrol Dial Transplant. 1999;14:2710-3. 20. Le Meur Y, Büchler M, Thierry A, et al. Individualized MMF dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007;7:2496-503. ** The first prospective randomized clinical trial documenting that thera­ peutic MPA monitoring can reduce the risk of MMF treatment failure and acute rejection episodes compared to fixed dose regimens. 21. Shaw LM, Figurski M, Milone MC, et al. Therapeutic drug monitoring of mycophenolic acid. Clin J Am Soc Nephrol. 2007;2:1062-72. * A position paper summarizing the actual evidence on the role of therapeutic drug monitoring of MPA. 22. Budde K, Tedesco-Silva H, Pestana JM, et al. Enteric-coated mycophenolate sodium provides higher mycophenolic acid predose levels compared with MMF: implications for therapeutic drug monitoring. Ther Drug Monit. 2007;29:381-4 23. Sánchez Fructuoso A, Calvo N, Moreno MA, et al. Better mycophenolic acid 12-hour trough level after enteric-coated mycophenolate sodium in patients with gastrointestinal intolerance to MMF. Transplant Proc. 2007;39:2194-6. 24. Cattaneo D, Merlini S, Zenoni S, et al. Influence of co-me­di­ca­tion with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transplant. 2005;5:2937-44.

25. Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol. 2007; 2:374-84. 26. Cattaneo D, Merlini S, Baldelli S, et al. Mycophenolic acid formulation affects cyclosporine pharmacokinetics in stable kidney transplant recipients. Ther Drug Monit. 2006;28:643-9. *The first paper documenting an impact of EC-MPS on cyclosporine pharma­ cokinetics. 27. Cattaneo D, Gaspari F, Zenoni S, Gotti E, et al. Two-hour blood cyclosporine level does not necessarily predict drug ex­posure and graft function outcome in stable kidney transplant recipients. Therapy. 2005; 2:95-105. 28. Puig JM, Mir M, Marin M, et al. Significant pharmacokinetic differences between MMF and enteric-coated mycophenolate sodium in stable renal transplant patients treated with ta­cro­li­mus with or without steroids. Am J Transplant. 2007;7:349. 29. Weimert NA, Derotte M, Alloway RR, et al. Monitoring of inosine monophosphate dehydrogenase activity as a biomar­ker for mycophenolic acid effect: potential clinical implications. Ther Drug Monit. 2007;29:141-9. 30. Glander P, Hambach P, Braun KP, et al. Pre-transplant inosine monophosphate dehydrogenase activity is associated with clinical outcome after renal transplantation. Am J Transplant. 2004;4:2045-51. * An important paper documenting a significant predictive role of MPA pharmacodynamic monitoring on complications of MMF therapy. 31. Akhlaghi F, Patel CG, Zuniga XP, et al. Pharmacokinetics of mycophenolic acid and metabolites in diabetic kidney transplant recipients. Ther Drug Monit. 2006;28:95-101. 32. Patel CG, Richman K, Yang D, et al. Effect of diabetes mellitus on mycophenolate sodium pharmacokinetics and inosine monophosphate dehydrogenase activity in stable kidney trans­plant recipients. Ther Drug Monit. 2007;29:735-42. 33. Morath C, Schwenger V, Beimler J, et al. Antifibrotic actions of mycophenolic acid. Clin Transplant. 2006;20:25-9.

61

Trends in Transplant. Transplantation 2008;2:62-8 2008;2

Cardiovascular Risk in Renal Transplantation Bengt C. Fellström1, Halvard Holdaas² and Alan G. Jardine³ ¹Dept. of Nephrology, University of Uppsala, Sweden; ²Dept. of Nephrology, University of Oslo, Norway; ³Dept. of Nephrology, University of Glasgow, UK

Abstract Renal transplant patients suffer from a higher risk of cardiovascular morbidity and mortality. The risk-factor spectrum is different from the general population; several risk factors are transplantation specific, and to a large extent dependent on the immunosuppressive drugs used to prevent rejection. Due to the complexity of the risk factors, the variable impact of each factor on different cardiovascular outcomes and the inter-relationships between risk factors, it is difficult to judge the overall cardiovascular risk in a single renal transplant patient. In this paper we review risk-factor data from the literature, limited to single risk factors and their impact on single cardiovascular outcomes. We believe that a cardiovascular risk calculator specific to the renal transplant population, which takes into account all the important risk factors for a cardiovascular event, based upon a high quality database such as the ALERT data set, may provide a solid guidance to means to assess the overall cardiovascular risk in renal transplant recipients. (Trends in Transplant. 2008;2:62-8) Corresponding author: Bengt C. Fellström, [email protected]

Key words Renal. Transplantation. Cardiovascular. Risk factor.

Correspondence to: Bengt C Fellström Professor of Nephrology University Hospital SE-75185 Uppsala, Sweden E-mail: [email protected]

62

Bengt C. Fellström, et al.: Cardiovascular Risk in Renal Transplantation

Introduction Patient and graft survival following renal transplantation have improved progressively over the last few decades, largely as a consequence of improved immunosuppressive agents. One result of the effective prevention of acute rejection episodes, however, is the emergence of longterm problems in renal trans­plantation, including graft failure due to chronic allograph nephropathy (CAN) and pre­mature patient death1-3. Mortality after renal transplantation is mainly due to cardiovascular disease (CVD), infections, and malignancies. In most countries that have active renal transplant programs, CVD are the predominant cause of pre­mature death4. An exception may be Australia, where malignancy (skin malignancies in particular) has been reported to be the dominating cause of patient death in some years. Ho­wever, CVD recently surpassed it as the leading cause of death. Although cardiovascular (CV) mortality is increased in renal transplant recipients (RTR) (3-5-times that of the general population), it is still significantly lower than in dialysis patients4,5, where mortality rates are 10-100-fold higher than the general po­pulation. The CV complications that affect RTR include myocardial infarction, left ventricular hypertrophy, heart failure, sudden (pre­sumed arrhythmic) cardiac death, stroke, and peripheral vascular disease. These different manifestations of CVD in RTR differ from the general population, both in their prevalence and the relationship between CV risk fac­tors and individual events. The spectrum of risk factors in RTR includes traditional risk factors (found in the ge­­neral population) such as age, smoking, male gender, hyperlipidemia, hypertension, dia­­betes, and preexisting CVD3. However, there are also risk factors that are transplantation-specific, such as the impact of immunosuppressive treatment on the CV risk, and the differing impact of individual agents on conventional CV risk factors6,7. Previously treated acute rejection episodes, graft loss, return to dialysis treatment, and the overall duration of re­nal replacement

therapy (RRT) have also been identified as CV risk factors in RTR. A useful way of classifying risk factors is to divide them into modifiable and non-modifiable risk factors, which gives direction to treatment or prevention of CV events in this population. A further important aspect in the assessment of CV risk is the interaction or co- va­riation between risk factors, as well as difficulties in comparing the relative influence of one risk factor versus another for future CV events. These problems encouraged us to develop a cardiovascular risk calculator based on the placebo group in the ALERT trial and comparable to the Framingham model used in the general population8. In the present review we will discuss some of the reported risk factors, how they are interrelated, and what may be done to reduce the influence of respective risk factors.

Age and gender Age and gender are clearly non-modifiable risk factors in the general population; age also seems to be an independent, non-modifiable risk factor for all CV events that occur in a renal transplant population9. In our experience, female gender has a hazard ratio of 0.75 with regard to both myocardial infarction and cardiac death, but no impact on non-CV death. Advanced age, on the other hand, was a significant risk factor for CV and non-CV death (HR: 1.27-1.95/decade). Older age was also a significant risk factor for the occurrence of stroke during the follow-up for the ALERT trial (unpublished results).

Time on renal replacement therapy Time on RRT has been implicated as a CV risk factor following renal transplantation10. This relationship has been suggested to be re­lated to remodeling of the vascular wall in uremic patients undergoing dialysis treatment. However, in the ALERT trial we could not show that time on RRT was related to either the frequency or incidence of nonfatal myocardial infarction or cardiac death9. Although total ti­me on RRT was a significant risk factor (HR: 1.06 per annum; p < 0.004) for noncardiac death in a univariate analysis, in a multi63

Trends in Transplantation 2008;2

variate analysis of risk factors of non-cardiac death, time on RRT did not emerge as a significant factor. Thus, in our understanding, there is still an uncertainty as to whether time on RRT has any influence on cardiac or non-cardiac cau­ses of death in RTR, on whether it is possible to “write off” risk accumulated on dialysis in those patients who survive to get a successful transplant.

Preexisting cardiovascular disease Several studies have reported that preexisting coronary heart disease (CHD) has a strong impact up on subsequent development of cardiac or coronary events after renal transplantation2,9,11,12. In the ALERT trial, preexisting coronary artery disease (CAD) was associated with a hazard ratio of > 3 for nonfatal myocardial infarction or cardiac death during follow-up. Prior cerebral vascular events were also independent risk factors for subsequent ischemic events. Thus, previous CVD must be recognized as a strong and important, albeit non-modifiable, risk factor for a variety of post­trans­plant CVD events (Table 1).

Diabetes mellitus Diabetes mellitus (DM) is a well-documented risk factor for several types of CV events in the general population9,13,14; a relationship that appears to hold in RTR. Since DM is the fastest growing cause of end-stage renal disease, we foresee an associated increase in posttransplant CV events. Furthermore, there is an increasing incidence of post­transplant diabetes mellitus (PTDM), partly due to the use of calcineurin inhibitors (specifically tacrolimus) and corticosteroid treatment in the prevention of rejection13,15. Posttransplant DM has comparable impact as a posttransplant CV risk factor to DM prior to renal transplantation, and is potentially reversible or preventable15. According to figures from U.S. Renal Data System (USRDS), the prevalence of PTDM one year after transplantation is 20-25% in adults, and three years following transplantation a prevalence of 30% PTDM has been reported. Similar findings are reported in pediatric transplant recipients, although the rate is lower (e.g. 10% at three years). In the ALERT trial, PTDM or preexist64

ing DM were strong independent risk factors for posttransplant, nonfatal myocardial infarction (HR: 2.41), for cardiac death (HR: 2.82), and also for stroke (both hemorrhagic and ischemic; HR: 3.9 and 4.5, respectively9,14. This translates into an overall significant risk for all causes of mortality (HR: 2.40; p < 0.001), attributable to DM, despite the fact that non-cardiac deaths were not dependent on DM. Thus, it is of great importance to prevent the development of end-stage renal disease in patients with DM and to consider non-diabetogenic immunosuppres­si­ve regimens where a patient is at risk or shows signs of PTDM.

Metabolic syndrome Metabolic syndrome is associated with increased risk of CV events in the general population. In the ALERT trial we identified metabolic syndrome according to the Adult Treatment Panel III 2001 definition (except that BMI ≤ 30 was used instead of waist circumference). Where three out of five of the criteria were fulfilled (BMI ≤ 30, triglycerides ≤ 1.7, HDL-cholesterol < 1.03 in males or < 1.29 in fe­males, sys­tolic blood pressure > 130 or diastolic blood pressure > 85 and glucose ≤ 110 mg/dl) in non­diabetic patients, then individuals were classified as having metabolic syn­dro­me. In patients with metabolic syndrome (498 of 1,718), 40% suffered a major adverse cardiac event (MACE), compared to 28% in pa­tients without metabolic syndrome (p < 0.001). Moreover, acute myocardial infarction and cardiac death were significantly more common during the follow-up in patients with metabolic syndrome compared to those without (42 vs. 28%; p < 0.006) and cardiac death was also significantly more common (47 vs. 28%; p ≤ 0.001). These are preliminary data which will be further analyzed with regard to which components of metabolic syndrome are more important than others, and the extent to which this classification adds to the risk attributable to conventional risk factors such as hyperlipidemia and obesity.

Lipid abnormalities In the general population, hypocholesterolemia (specifically elevated LDL cholesterol and low

Bengt C. Fellström, et al.: Cardiovascular Risk in Renal Transplantation

Table 1. Semiquantitative summary of risk factors versus cardiovascular disease events in renal transplant patients Risk factors

Nonfatal myocardial infarction

Cardiac death

MACE

Ischemic stroke

Hemorrhagic stroke

All cause mortality

Age

+

+

+

+

0

+

Previous CVD

+

+

+

?

?

+

LVH

0

+

+

0

+

+

DM

+

+

+

+

+

+

Metab. Syndr.

+

+

+

?

?

+

Hyperlipidemia

+

+

+

0

0

0

Hypertension

0

0

0

0

+

0

Renal dysfunction

0

+

+

+

0

+

MACE: major adverse cardiac events; CVD: cardiovascular disease; LVH: left ventricular hypertrophy: DM: diabetes mellitus; +: positive risk factor; 0: neutral as risk factor.

HDL cholesterol) is associated with increased CV risk. Although the literature in RTR16,17 is less clear, recent large studies6 tend to support an adverse effect of hyperlipidemia on CVD and suggest that previous ne­gative studies (e.g. Kasiske, et al.3 1996) may be a consequence of pooling CV endpoints with disparate determinants. Posthoc analyses of the ALERT trial9,11,12 demonstrated that total cholesterol and LDL cholesterol were significant risk factors for nonfatal myocardial in­farction, but had less impact on cardiac death or stroke. In contrast, lipid abnormalities were not related to nonCV deaths. In a multivariate analysis, elevated LDL cholesterol value was an independent risk factor both for MACE and nonfatal myocardial infarction, with a hazard ratio of 1.35 per mmol/l increase in LDL cholesterol. Conversely, the risk of stroke was not related to LDL cholesterol values at baseline. Thus, in summary, LDL cholesterol is a risk factor for ischemic coronary events rather than other CV events, and it is ischemic coronary events that are modifiable by lipid lowering in this population.

Hypertension Hypertension is a well-documented CV risk factor in the general population. However, the situation is not as clear in a renal transplant population. Hypertension is more prevalent in transplant patients compared with the general population (2-4-fold). In contrast to hyperlipid-

emia, hypertension did not seem to be a risk factor for nonfatal myocardial infarction in the ALERT trial, but systolic blood pressure and pulse pressure9 were determinants of stroke (HR: 1.34/10 mm hg) and cardiac death. The relationship with cardiac death is likely to be linked to left ventricular hypertrophy, associated fibrosis, and the development of arrhythmias. The differential effect of hypertension and hyperlipidemia on specific CV events in this population is an important observation with implications for risk management. Thus, hypertension is a risk factor for stroke and cardiac death in renal transplant patients, whereas the principal risk factor for myocardial infarction is hyperlipidemia.

Renal transplant dysfunction and graft loss Reduced renal function has been reported in several investigations to be strongly related to CVD in the general population18,19. This is true both in individuals with only a small reduction of renal function19, as well as those patients on dialysis treatment5. In the latter group, it is well established that the rate of CVD is extremely high, disproportionately so in younger patients8. The spectrum of risk factors for CV complications of renal insufficiency may differ from the situation in a non-renal population20. For example, total cholesterol has even been shown to be inversely re­ 65

Trends in Transplantation 2008;2

lated to CVD in patients on maintenance hemodialysis. In contrast, systemic inflammation, reflected by increased C-reactive protein or interleukin-6 levels is also strongly associated with cardiovascular risk in patients with renal insufficiency21. The CVD in renal insufficiency is also characterized by an excessive calcification of small and large arteries, in particular coronary arteries, rather than simple atheromatous CAD. This is due to calcium, phos­phate and parathyroid hormone abnormalities, as well as inadequate synthesis and levels of calcification inhibitors such as fetuin and N-methylpurine-DNA glycosylase (MPG)22. Due to the high quality of data in the ALERT trial we were able to analyze the relationship between moderate renal dysfunction at baseline and the different CV events that were captured during the follow-up23. Similar data have been presented from registry studies made on USRDS data24. We demonstrated that renal dysfunction, assessed by increased creatinine levels at baseline, was a significant and independent risk factor both for MACE, cardiac death and all-cause mortality (HR: 1.9-2.9 per 100 umol/l creatine; p < 0.0001). In a recent as yet unpublished ana­ lysis it seems that renal dysfunction is an independent risk factor for ischemic rather than hemorrhagic stroke. However, renal dysfunction was not a risk factor with regard to nonfatal myocardial infarction. There seems to be a threshold serum creatinine le­vel of 200 umol/l, above which the risk of cardiac death (and all cause mortality) was tripled12. In a subsequent ana­ lysis14, the relative importance of increased creatinine levels was compared to the relative risk in diabetes for cardiac death, MACE, and allcause mortality. It could be shown that serum creatinine levels of 125-135 umol/l confer the same CV risk as DM for MACE, cardiac death and all-cause mortality. Furthermore, severe dysfunction as a consequence of graft loss was associated with a doubling of the risk of myo­ cardial infarction, MACE, and all-cause mortality compared to patients with a functioning graft23. Taken together, the importance of renal dysfunction as a risk factor for MACE, cardiac 66

death, and all-cause mortality cannot be underestimated. Transplant function should be considered a modifiable CV risk factor in this population that not only impacts on the risk for graft loss15, but also on patient survival.

Immunosuppressive agents The various immunosuppressive agents that are used in renal transplantation have been documented to have an impact on conventional CV risk factors. The effects are upon blood pressure, lipoprotein profile, diabetes, hy­pertension and renal dysfunction hyperlipidemia, and also on graft function and PTDM. The effects on blood pressure, lipoprotein profile and diabetes differ between the various agents used in organ transplantation (Ta­ble 2). It has been well documented that calcineurin inhibitors (CNI), including both cyclosporin and tacrolimus, interfere with lipid metabolism and also contribute to resistant hypertension. Whether there is a difference between cyclosporin and tacrolimus is a matter of debate25-27. It has been claimed that the effects on lipid metabolism and hypertension may be more evident with cyclosporin than tacrolimus, although there are no reports linking these effects on risk factors to “hard” outcome variables such as CV events. The mechanism by which CNI affect lipid metabolism has been reported be mainly due to interference with LDL-receptor sensitivity and impaired activity of lipoprotein lipase28. Calcineurin inhibitors may also cause hypertension by sodium and water retention, vasoconstriction in the vascular wall, and possibly sympathetic activation29. It has also been claimed that long-term use of CNI may have an adverse effect on endothelial function, possibly related to the influence by CNI on glucose metabolism. In fact, both tacrolimus and cyclosporine contribute to an increased incidence of PTDM30. The cause of DM in CNI-treated individuals may be due to an effect on insulin release together with insulin resistance. The dependence of insulin release on FK binding-protein 12 probably ex­plains the observation that tacrolimus cau­ ses more PTDM than cyclosporin, and tacrolimus use was clearly shown to impair insulin secretion in the DIRECT study. However, the extent to which

Bengt C. Fellström, et al.: Cardiovascular Risk in Renal Transplantation

Table 2. Semiquantitative estimation of influence by immunosuppressive agents on cardiovascular risk factors in renal transplantation Drug/Agent

Hypertension

Hyperlipidemia

Diabetes

Renal dysfunction

Cyclosporine

++

++

+

+

Tacrolimus

+

+

++

+

Sirolimus /Everolimus

0

+++

0

0

Corticosteroids

+

++

+++

0

Mycophenolate mofetil

0

0

0

0

Monoclonal Ab

0

0

0

0

0: neutral effect; +, ++, +++: degree of enhanced effect.

differences in PTDM translate into wor­se long-term CV outcome is less clear. Corticosteroids are also used in almost all patients undergoing organ transplantation. Corticosteroids are known to induce peripheral insulin resistance and subsequently type II-like DM. Corticosteroids also cause dyslipidemia, principally increased levels of VLDL tri­glycerides and increased LDL cholesterol. However, corticosteroids increase all choleste­rol subfractions, a phenomenon most clearly seen in the early posttransplant period (SOLAR study). Corticosteroids also cause hy­per­ten­sion through salt and water retention and enhanced receptor function, the pattern of hypertension and hyperlipidemia being akin to that seen in Cushing’s syndrome31. Mammalian target of rapamycin (mTOR) in­hibitors such as sirolimus and everolimus are both documented to cause hypercholeste­ro­lemia and hypertriglyceremia. This is strong­ly dose-dependent and is less of a clinical problem at current dosage levels32-34. The pattern of dyslipidemia is also atypical with a disproportionate effect on HDL such that the overall pattern, together with the antiproliferative effects of vascular cells, may be cardioprotective (as it is in experimental animals35). The mTOR inhibitors appear to have little effect on blood pressure or PTDM and do not cause nephrotoxicity. However, any long-term effects on CV events remain to be established. Other immunosuppressive agents such as mycophenolate mofetil and monoclonal antibodies directed towards CD20 and CD25, and

monoclonal antibodies directed against receptors of the co-stimulatory pathway of T-cell activation (Belatacept), all seem to be neutral with regard to CV risk factors. In summary, CNI, mTOR inhibitors and corticosteroids all seem to have an adverse influence on CV risk factors, whereas other immunosuppressive agents used in organ trans­plantation seem to be neutral. However, to the best of our knowledge there are no data to show that these adverse effects on risk factors actually translate into an increased incidence of “hard” CV events or CVD, although modification of immunosuppression is one option when managing CV risk in RTR.

Cardiovascular risk calculator The Framingham risk factor model used in the general population is not applicable in a renal transplant population, since their risk factor profile (and the impact of risk factors on CV events) is different, and there are risk factors which are transplantation specific. For that reason we are developing a risk calculator, similar to the Framingham model, but targeting RTR and based upon the high quality data set from the ALERT trial. This work is ongoing, but may offer a way of identifying specific risk in individual patients and optimizing treatment, both conventional CV treatment and CV modification of immunosuppression, to prevent future events. In summary, RTR suffer from a higher risk of CVD and mortality. The spectrum of risk fac67

Trends in Transplantation 2008;2

tors is different from the general population. Several risk factors are transplantation-specific and, to a large extent, dependent on the drugs used to prevent allograft rejection. Due to the complexity of the risk factors, the differential impact of each factor, the co-variability between risk factors and the differences of risk factors for different CV manifestations, it is difficult to judge the risk in a single renal transplant patient. We believe that a risk calculator which takes into account all the important risk factors for CV events, based upon a high quality database such as the ALERT data set, may be invaluable when trying to assess and manage the overall CV risk in a re­nal transplant patient.

References

1. Fellström B, Jardine A, Holdaas H. Chronic allograft nephropathy. Evidence Based Nephrology. BMJ Books. 2008 [in press]. 2. Lindholm A, Albrechtsen D, Frodin L, Tufveson G, Persson NH, Lundgren G. Ischemic heart disease–major cause of death and graft loss after renal transplantation in Scandinavia. Transplantation. 1995;60:451-7. *Reference of interest. 3. Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after renal transplantation. J Am Soc Nephrol. 1996;7:158-65. **Reference of great interest. 4. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis. 1998;32:853-906. 5. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32:S112-19. 6. Hilbrands LB, Demacker PN, Hoitsma AJ, Stalenhoef AF, Koene RA. The effects of cyclosporine and prednisone on serum lipid and (apo)lipoprotein levels in renal transplant recipients. J Am Soc Nephrol. 1995;5:2073-81. 7. Miller LW. Cardiovascular toxicities of immunosuppressive agents. Am J Transplant. 2002;2:807-18. 8. Soveri I, Fellstrom B, Holdaas H, Jardine AG, Holme I. Cardiovascular risk calculator in renal transplantation calculator. Abstract. J Am Soc Nephrol. 2007. 9. Jardine AG, Fellström B, Logan JO, et al. Cardiovascular risk and renal transplantation: post-hoc analyses of the ALERT study. Am J Kidney Dis. 2005;46:529-36. **Reference of great interest. 10. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation. 2002;74: 1377-81. 11. Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial. Lancet. 2003;361:202431. **Reference of great interest. 12. Holdaas H, Fellstrom B, Cole E, et al. Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study. Am J Transplant. 2005;5:2929-36. 13. Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am. J. Transplant. 2003;3:178-85. *Reference of interest. 14. Soveri I, Holdaas H, Jardine A, Gimpelewicz C, Staffler B, Fellström B. Renal transplant dysfunction – importance quantified in

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comparison with traditional risk factors for cardiovascular disease and mortality. Nephrol Dial Transplant. 2006;21:2282-9. 15. Cosio FG, Kudva Y, Velde M, et al. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. DIRECT study. Kidney Int. 2005;67):2415-21. *Reference of interest. 16. Mathis AS, Dave N, Knipp GT, Friedman GS. Drug-related dyslipidemia after renal transplantation. Am J Health Syst Pharm. 2004;61:565-85. 17. Holdaas H, Fellström B, Jardine A. Lipid abnormalities in solid organ transplant recipients. Clin Lipidol. 2007 [in press]. 18. Weiner DE, Tighiouart H, Amin MG, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol. 2004;15:1307-15. *Reference of interest. 19. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. *Refer­ ence of interest. 20. Longenecker JC, Coresh J, Powe NR, et al Risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol. 2002;13:1918-27. *Refer­ ence of interest. 21. Honda H, Qureshi AR, Heimbürger O, et al. Serum albumin, Creactive protein, IL-6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis. 2006;47:139-48. **Reference of great interest. 22. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-83. 23. Fellström B, Holdaas H, Jardine A, et al. ALERT Study Group. Renal dysfunction is a strong and independent risk factor for mortality and cardiovascular complications in renal transplantation Am J Transplant. 2005;5:1986-91. 24. Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation. 2003;75:1291-5. 25. Kasiske BL, Tortorice KL, Heim-Duthoy KL, Awni WM, Rao KV. The adverse impact of cyclosporine on serum lipids in renal transplant recipients. Am J Kidney Dis. 1991;17: 700-7. 26. Vathsala A, Weinberg RB, Schoenberg L, et al. Lipid abnormalities in cyclosporine-prednisone-treated renal transplant recipients. Transplantation. 1989;48:37-43. 27. Artz MA, Boots JM, Ligtenberg G, et al. Conversion from cyclosporine to tacrolimus improves quality-of-life indices, renal graft function and cardiovascular risk profile. Am J Transplant. 2004;4:937-45. 28. Vaziri ND, Liang K, Azad H. Effect of cyclosporine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions. J Pharmac Exp Ther. 2000;294:778-83. 29. Sander M, Lyson T, Thomas GD, Victor RG. Sympathetic neural mechanisms of cyclosporine-induced hypertension. Am J Hypertens. 1996;9:121-38S. 30. van Hooff JP, Christiaans MH, van Duijnhoven EM. Tacrolimus and posttransplant diabetes mellitus in renal transplantation. Transplantation. 2005;79:1465-9. *Reference of interest. 31. Fellström B. Risk factors for and management of posttransplantation cardiovascular disease. Bio Drugs. 2001; 15:261-78. 32. Johnson RW, Kreis H, Oberbauer R, et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation. 2001;72:777-86. 33. Hoogeveen RC, Ballantyne CM, Pownall HJ, et al. Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Transplantation. 2001;72:1244-50. 34. Morrisett JD, Abdel-Fattah G, Hoogeveen R, et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res. 2002;43: 1170-1180. 35. Pakala R, Stabile E, Jang GJ, Clavijo L, Waksman R. Rapamycin attenuates atherosclerotic plaque progression in apolipoprotein E knockout mice: inhibitory effect on monocyte chemotaxis. J Cardiovasc Pharmacol. 2005;46:481-6.

Trends in Transplant. Pilar Isla 2008;2:69-77 Pera, et al.: Quality of Life in Simultaneous Pancreas-Kidney Transplant Recipients

Quality of Life as an Indicator of the Effectiveness of Simultaneous Pancreas-Kidney Transplantation Pilar Isla Pera1, Joaquin Moncho Vasallo2, Alberto Torras Rabasa3,4 and María José Ricart Brulles3 1

Public Health Department, Nursing School, Barcelona University, Barcelona, Spain; 2Community Clinic, Preventative Medicine and Public Health and History of the Science, Nursing School, Alicante University, Alicante, Spain; 3Clinical Institute of Nephrology and Urology, Barcelona Hospital Clinic, Barcelona, Spain; 4Faculty of Medicine, Barcelona University, Barcelona, Spain

Abstract The meaning of quality of life has evolved to become a multidimensional and integrative concept that includes both objective and subjective criteria. Simultaneous pancreas-kidney transplantation aims not only to increase survival but also to improve health-related quality of life. Studies of health-related quality of life in simultaneous pancreas-kidney transplantations show that the improvement achieved in some dimensions can surpass values in the general population, but without reaching overall levels of health-related quality of life in this population. Qualitative studies and those analyzing psychological variables show that many patients have anxiety or identity disorders. Simultaneous pancreas-kidney transplant recipients fear graft loss, and the transplant represents not just physical but also imaginary and symbolic implantation of the other person’s organs. Health-related quality of life assessments show that age, gender, years since diabetes onset, time under renal replacement therapy, and time since simultaneous pancreas-kidney transplantation have significant effects. Future studies should perform temporal evaluations to determine the variations produced after simultaneous pancreas-kidney transplantation and combine quantitative and qualitative methods to provide more exhaustive information on this topic. (Trends in Transplant. 2008;2:69-77) Corresponding author: Pilar Isla Pera, [email protected]

Key words Quality of life. Health-related. Transplantation. Pancreas. Kidney.

Correspondence to: Pilar Isla Pera Departamento de Salud Pública Escuela de Enfermería Campus de Ciencias de la Salud de Bellvitge Universidad de Barcelona Feixa Llarga, s/n Hospitalet de Llobregat 08907 Barcelona, Spain E-mail: [email protected]

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Introduction Diabetes mellitus (DM) is one of the main causes of terminal renal failure. At 10-15 years after DM onset, diabetic nephropathy affects 30% of patients and, when these patients require renal replacement therapy (RRT), survival is lower than that in nondiabetic patients1. Currently, the 2000 and 2003 recommendations of the American Diabetes Association (ADA) establish that simultaneous pancreas-kidney (SPK) transplantation should be considered the treatment of choice in diabetic patients under RRT with dialysis, while pan­creatic transplantation alone should be considered in diabetic patients without terminal renal failure but with unacceptably poor metabolic control and quality of life (QOL)2. Islet cell transplantation is still considered an experimental treatment3,4. The indications for SPK transplantation center on patients with diabetes mellitus type 1 (DM1) and terminal renal failure, but do not exclude patients with diabetes mellitus type 2 (DM2) and terminal renal failure. The aim of SPK transplantation is to restore renal function and blood glucose levels to normal values, allowing insulin and dialysis therapy to be discontinued, some of the complications of DM1 to be stabilized or improved, and healthrelated quality of life (HR-QOL) to be increased. For patients and their families, SPK transplantation is an idealized solution to end the physical and psychological distress cau­sed by the disease. This procedure represents the recovery of “health” and freedom, the end of suffering, and not having to depend on a machine or on insulin to continue living5. However, a functioning SPK transplant is not synonymous with cure, since the complications of DM1 may persist, immunosuppressive therapy carries secondary risks, the need for life-long medication and medical followup continues, and some patients may experience physical and/or psychological disturbances. Since the first pancreas transplant in 1966, more than 25,000 diabetic patients throu­ghout the world have undergone this procedure. In Spain, the first pancreatic transplant was performed in the Hospital Clínic de Barcelona in 1983. Since then, 70

more than 600 pancreatic transplants have been performed, most of which have been SPK transplants4-6. From 2000, the number of pancreatic transplants performed rose substantially, increasing from an average of 22.7 per year in the period 1993-1999 to 94 in 2006. Of the 540 pancreatic transplants performed between 1999 and 2006, 472 were SPK, 48 were pancreatic, and 20 were multiorgan transplantations6. In Spain, 68% of kidney transplants and 70% of pancreatic transplants continued to function at five years6. In the Hospital Clínic de Barcelona, from 2000-2006, one-year survival in patients, kidney transplants, and pancreatic transplants was 97.8, 95.6, and 89.7%, respectively, and five-year survival was 97.8, 89.7, and 86.8%, respectively7. Health professionals have traditionally given priority to the study of clinical features in transplant recipients. However, in the last decade, interest in patients’ subjective perception of QOL has increased. Health-related quality of life assessment has emerged as a new medical indicator of therapeutic and health services’ effectiveness8. It includes the aspects of QOL most closely related to the experience of the disease and to the treatment and follow-up required – aspects which could potentially be modified by the health system.

Evolution of the concept of quality of life Interest in the study of QOL, or the “good life” goes back to ancient times. Aristotle stated that to achieve human happiness, certain external elements influencing happiness were required9. However, the current concept of “quality of life” and scientific interest in its measurement is relatively recent. In the 1950s, concerned by growing industrialization and the social changes generated after the Second World War, some social researchers undertook studies aimed at determining the population’s wellbeing. At first, these studies used objective, quantifiable, economic and social indicators. In 1954, the United Nations constructed a system of indicators to measure QOL that included the dimensions of health, diet, working conditions, housing, leisure time, social

Pilar Isla Pera, et al.: Quality of Life in Simultaneous Pancreas-Kidney Transplant Recipients

security, transport, human freedoms, the environment, and education10. Thus, the level of life was defined as the point at which the population’s overall needs were met. These studies progressively evolved, leading to the notion of “quality of life”, understood as a multidimensional and integrative concept that includes both objective and subjective criteria. Quality of life evaluations consider the subject’s material environment together with the social environment, viewing the person as an active subject and protagonist of action. Calman11 defined QOL as “the gap between a person’s expectations and achievements”. Health status and disease have classically been evaluated through quantitative data on morbidity, disability, mortality, and survival in individuals or populations and the results have been interpreted by health professionals. However, these data are insufficient to evaluate health, which is a complex, multidimensional, and constantly evolving concept. In 1946, the World Health Organization defined health as “a state of complete physical, mental, and social wellbeing and not just the absence of disease”12. This definition viewed health in positive terms and included social and mental dimensions, but did not manage to satisfy all collectives. The difficulty of finding a satisfactory definition of health is not due to a semantic problem, but rather to the nature of health as a polymorphous and changing state, making it a complex reality. A study performed in Barcelona (Spain) with distinct population groups revealed that health is a multidimensional concept involving physical, psychological, social, educational, economic, political, religious, and philosophical factors and varies according to group13. Blaxter14 indicates the importance of psychological and social factors and states that health is a fluid concept that depends on variables such as age and sex. For Modolo15, health is a cultural concept linked to the needs of people and their environment as well as being a way of perceiving and dealing with these needs. After health was recognized to be much more than the absence of disease and that its meaning differs from one society to another – even

among persons from the same social group – the concept of HR-QOL appeared in the 1970s. However, there is no absolute consensus on the conceptual model of HR-QOL or on how it should be measured. For Patrick and Erickson16, HR-QOL is the value assigned to duration of life modified by the impairments, functional states, perceptions, and social opportunities that are influenced by disease, injury, treatment, or policy”. For Whiting17, HR-QOL is the measurement and quantification of the subjective perspective of patients on distinct aspects related to health. After reviewing the definitions, Shumaker and Naughton18 proposed the following: subjective evaluation of the influence of health status, healthcare, and health promotion on the ability of individuals to maintain a level of functioning that allows them to perform activities important to them, and that affects their general wellbeing. The most important dimensions that include HR-QOL are: social, physical, and cognitive functioning, mobility and self-care, and emotional wellbeing. Although different, the most important aspects of all definitions are that they emphasize the subjective evaluation ma­de by an individual of his or her own QOL and include a limited and defined number of dimensions.

Measurement of health-related quality of life Health-related quality of life is usually measured through standardized questionnaires, either self-administered or administered through a personal interview. Several instruments to establish an approach to HR-QOL measurement have been developed, mainly in Anglo-Saxon countries. These instruments can be divided into generic and specific. Specific instruments focus on aspects of QOL related to a specific disease or clinical situation; these instruments can be specific to a disease (transplants, diabetes, cancer, is­chemic heart disease), to a function (sexuality, fatigue, treatment adherence), or to a population group (adolescents, the elderly). In contrast, generic instruments are independent of diagnosis and consequently can be applied to any population or disease20. Specific questionnaires lack the breadth of generic instruments, but can be more sensitive 71

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to the aspects of QOL influenced by a specific disease21. Independently of whether or not there are specific instruments to evaluate HR-QOL, selecting the most suitable instrument in a particular context or situation is essential. According to Donovan, et al.22, the characteristics of a good instrument for measuring QOL are suitability to the health problem to be measured, and accuracy, validity, and sensitivity in detecting changes over time or among individuals; these instruments should also be based on data generated by the patients themselves and be well accepted by patients, health professionals, and researchers. The use of original HR-QOL instruments in other cultures, countries, or languages requires that they be validated, a process for which a series of guidelines on their translation, adaptation and evaluation of the measurement properties have been established. In 2002, the Scientific Advisory Committee of the Medical Outcomes Trust23 defined eight necessary attributes that should be taken into account to validate a HR-QOL instrument: conceptual model, validity, reliability, sensitivity to change, interpretability, administration, alternative formats, and cross-cultural adaptation.

Clinical utility of health-related quality of life evaluation Several authors have identified problems that could limit the systematic application of HRQOL evaluation in clinical practice. Among these are the difficulty of administering excessively long questionnaires that burden patients and are timeconsuming for health professionals, logistic and economic problems in data analysis, and the lack of immediate results24. Criticisms have also been made due to methodological difficulties and the consequent biases that can be produced by measuring HR-QOL25, the lack of specific definitions of this concept in the various studies, and the lack of attention paid to the patients’ feelings26. Health-related quality of life is essentially a subjective concept but, despite the difficulties and problems posed, measurement of this concept is arousing growing interest in medical research because the data obtained are an important source 72

of information for research related to health services27. Systematic measurement of HR-QOL in patients could benefit the process of medical care28,29. The results of HR-QOL research could aid the diagnosis of previously undetected functional and emotional problems, treatment followup, monitoring of disease progression and treatment response, and could improve communication between health professionals and health services users30-32. Several theoretical models have been proposed to systematize the clinical use of HRQOL evaluation33,34. Callaghan, et al.33 identified three stages in the application of HR-QOL results in clinical practice: firstly, the results of perceived health are transformed into specific diagnoses (link to evaluation); secondly, the health professional evaluates the needs perceived by the patients and the need for resources aimed at the specific causes of the dysfunction and plans interventions (link to resources); and thirdly, the health professional and user decide whether a new treatment should be started (link to action). One of the greatest benefits expected from the clinical application of HR-QOL evaluation would be that of providing additional and hitherto unknown information to health professionals35-38. Several studies have been performed of the impact of HR-QOL evaluations before consultations on doctor-patient communication39,40. In a study performed in patients with epilepsy, 63% of the physicians stated that the HR-QOL test had provided new information41. Equally, in transplant recipients, HR-QOL evaluation provided additional information that could not have been obtained through physiological measures42. Studies performed in oncology patients revealed that if the physician bore the results of the HR-QOL evaluation in mind, communication and the patient’s HR-QOL improved over a six-month period43. A review of 21 studies showed that when physicians knew the results of HR-QOL assessment, they made more diagnoses, especially related to mental health, and the services provided increased. However, no scientific evidence was found on the effect of HR-QOL assessment on patients’ functional status or health44.

Pilar Isla Pera, et al.: Quality of Life in Simultaneous Pancreas-Kidney Transplant Recipients

Despite the theoretical conceptualization and the importance that HR-QOL assessment has acquired in the last few decades, as well as the increase in the number of publications on the subject, the effects on clinical practice have been scarce45 except in oncology. Numerous studies of HR-QOL have been performed in transplantation, including some qualitative investigation, but little research has been performed on the contribution of HR-QOL evaluation to transplant-related clinical practice46.

Results of questionnaire-based health-related quality of life assessment in simultaneous pancreas-kidney transplant recipients To measure HR-QOL and explore the experience of disease and of SPK transplantation, we performed an observational, cross-sectional, ethnographic qualitative study in the Hospital Clínic de Barcelona between 2004 and 20055. All patients who had undergone transplantation between 1998 and 2002 and in whom both grafts continued to function were included in the HRQOL study. During this period, 90 SPK transplants were perfor­med in the Hospital Clínic de Barcelona. At the start of the study, both grafts were functioning in 71 patients (78.8%). Of this group, two patients were excluded because they were followed-up in another province. The sample was composed of 69 patients, 41 men with a mean age of 41.78 ± 6.5 years, and 28 women with a mean age of 38.5 ± 7 years. Time since SPK transplantation ranged from 2-6 years. For the qualitative study, 10 patients with good communication skills (two for each year of the study) were selected. To evaluate HR-QOL, the SF-36 questionnaire was used. This was chosen because it is the most widely used instrument to evaluate HR-QOL in patients with DM1 and terminal renal failure under RRT as well as in patients with kidney and SPK transplants47. The psychometric properties of this questionnaire have been evaluated in more than 400 articles48 and all publications on the metric characteristics of the Spanish version of

the SF-36 demonstrate its reliability, validity, and sensitivity49. For the qualitative study, an intensive case study was performed based on qualitative techniques: in-depth interviews, ethnographic descriptions, and participant observation. In our study, 66.6% of the patients believed that their health was better than in the previous year and only 8.4% thought it had worsened. Multivariate analysis demonstrated that SPK transplantation was significantly associated with improved HR-QOL in all health dimensions50. These results coincide with tho­se of other studies showing better results in patients with terminal renal failure who recei­ved transplants than in those who remained under RRT with distinct dialysis techniques51-54 and also coincide with those of studies sho­wing the effectiveness of SPK transplantation in improving HR-QOL7,55-59, achieving, in some dimensions, HR-QOL similar or even superior to that in the general population. Nevertheless, both our results and those of other authors show that overall HR-QOL is lower in transplant recipients than in the general population7,53-60. In our study, the perception of general health was lower in men and women with SPK transplantation than in the Spanish general population. Health-related quality of life does not depend on SPK transplantation alone. Multivariate analysis shows that in addition to SPK transplantation, other variables have a significant effect. These variables include, age, gen­der, years since onset of DM1, length of time under RRT, time since SPK transplantation, and socioeconomic factors.

Gender In our study, female gender was negatively associated with the dimensions of mental health, bodily pain, vitality, role-emotional and physical function50. In some studies in kidney transplant recipients, no differences were found according to sex, and better HR-QOL was even observed in women, mainly in the dimension of mental health42,61. However, in most publications, female gender is associated with worse perceived health and HR-QOL, both in healthy individuals and female patients27,49,62. 73

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In men, the values for role-physical and role-emotional were significantly lower than those in the Spanish general population, even though values for the dimension of vitality were significantly higher than the mean for the Spanish general population. Women showed lower values than men in all dimensions of the test. However, fewer significant differences were found with the Spanish general population, possibly due to the smaller number women in the sample, which reduced statistical power50.

Age Age has frequently been associated with worse QOL49,62-65. In our study, age sho­wed a negative but non-significant (p = 0.051) association with general health, but a positive association with mental health50. This finding could be due to the relative youth of SPK transplant recipients. The negative effects of age on HRQOL could be due to the effect of functional deterioration produced in older persons and not just to the effect of the disease, although the SF-36 may be able to discriminate between the effect of disease and treatment and that of age on HR-QOL42. The association between older age and better HR-QOL has been observed in patients under RRT and in kidney transplant recipients42,61, and would be in agreement with other studies showing that having a chronic disease and being young is associated with psychological disorders and worse HR-QOL66-69. This association could be explained by the difficulty of young persons in having to cope with chronic health problems while still attempting to forge a life for themselves.

Years since onset of diabetes mellitus type 1 and length of time under renal replacement therapy In our study, time since onset of DM1 was negatively associated with the dimensions of mental health and bodily pain. No significant differences were found due to length of time under RRT50. Other studies of kidney transplant recipients have reported an association between length of time under RRT and a lower 74

overall physical score42 in HR-QOL assessment and an increase in posttransplantation psychological disorders70. Some studies suggest that patients with prolonged treatment experience difficulties in adapting to the disease, treatment, lifestyle, and the stigma attached to their illness71,72. Although SPK transplant recipients must also continue under treatment, RRT involves greater dependency and more apparent stigma.

Time since simultaneous pancreas-kidney transplantation In our study, the highest HR-QOL scores were observed in patients with the most recent transplants. Patients receiving a graft in the previous year had values higher than those in the Spanish general population in the dimensions of role-physical, vitality, and role-emotional; a negative association was found in the dimension of physical function and no significant differences were found in the remaining dimensions, including perception of general health50. These results are in agreement with those of other studies reporting reduced HR-QOL with the passage of time in patients receiving some type of transplantation8,61,73-75. Some studies report that transplant recipients experience a state of euphoria in the first year after the procedure due to improvements in physical, social, sexual function, and employment76,77 and that HR-QOL scores tend to reach a peak and then decline77. Other studies have shown that HR-QOL in transplant recipients undergoes temporal oscillations. A study in kidney transplant recipients showed that HR-QOL improved dur­ing the first six months after the procedure, then declined, and began to improve again three years after the procedure78.

Socioeconomic factors Although some studies have reported no association between socioeconomic factors and HR-QOL42, others have found a strong correlation between socioeconomic position and HRQOL79. Our study did not include socioeconomic variables.

Pilar Isla Pera, et al.: Quality of Life in Simultaneous Pancreas-Kidney Transplant Recipients

Results of perceived health and quality of life after simultaneous pancreas-kidney transplantation based on qualitative studies In our study, we found that SPK transplantation leads to a restructuring of the recipient’s experience. After years of disease, complications, and disability, a new kidney and pancreas are surgically implanted and the patient stops being diabetic and his or her terminal renal failure is cured. To describe this new situation, patients use the words miracle, reborn, or living again. Patients report that they have not only regained their “health”, but also their skin color, the gleam in their eyes, vitality, social relationships, and, in some cases, sexual and reproductive function5. However, after SPK transplantation, the complications of DM1, surgery and treatment persist to a greater or lesser extent, as do psychological disorders in some patients. The SPK transplant recipients fear graft loss and live with two organs from a cadaver that may differ from them in sex and age. The transplant entails not merely the physical but also the imaginary and symbolic implantation of another person’s organs. In some patients, all of these factors can lead to anxiety and identity disorders. Nevertheless, patients minimize the problems because they compare them with their pretransplant situation. The change of life after SPK transplantation is also expressed with new perceptions to the extent that some values are lost and others adopted (spending time with friends and family, taking walks and being able to enjoy life again). For these patients, medicine is highly effective both scientifically and symbolically5. Other qualitative studies have also shown that SPK and kidney transplant recipients viewed the transplant as a gift of life and described themselves as being “reborn”66,80. Nevertheless, there are also qualitative and quantitative studies that have described psychological problems, the difficulty of constructing a new identity, and identification with the donor in transplant recipients60,80-84.

Summary The aim of SPK transplantation is not only to increase survival but also to improve patients’ HR-QOL. A good balance between functional efficacy of the graft and the patient’s physical and psychological integrity are required8. An assessment of HR-QOL is important as it offers a person-centered rather than a disease-centered health outcome and provides information on how the patient feels independently of clinical data85. The HR-QOL is frequently used as a synonym of self-perceived health, which has been shown to be useful in predicting morbidity and mortality in patients with terminal renal failure86-89. In general, HR-QOL questionnaires have certain limitations, given the difficulty of being sufficiently flexible to adjust to the specific context in which patients live and cope with their disease, and the difficulty of knowing and understanding complex physical, psychological, and functional variables through a simple numerical evaluation. Moreover, HR-QOL instruments only evaluate the dimensions that patients experience directly and exclude other variables that also affect their health such as certain biological and socio-environmental characteristics. The aim of qualitative research is not to explain phenomena and generalize the results, but rather to understand phenomena, incorporating the other’s perspective, bearing in mind the socio-cultural components and reality of the context in which these phenomena are produced. Qualitative investigation allows researchers to gain access to the world of emotions, feelings, and daily experiences, and insight into the impact of advanced technologies in patients, their facilities, and the social milieu of the individuals involved; this type of research also aids reflection on the social role of health professionals’ practice. Listening to the patient’s suffering can also help health professionals to be more human and authentic90. Interest in questionnaire-based HR-QOL evaluation lies in the possibility of registering patients’ perceptions quantitatively or semiquantitatively; the results can be communicated and used 75

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in practice for the purposes of description, evaluation, or comparison91. Qualitative research is more appropriate to understand patients’ experience of the disease and their perceptions, beliefs, and needs, but is more complex and cannot cover the patients’ entire universe. In future, temporal evaluations should be performed to determine the variations produced over time after SPK transplantation. Quantitative and qualitative methods should be combined, and the perspective of gender should be investigated to understand the differences in the experience of disease and perceived health and QOL between men and women.

Acknowledgements All the authors participated in the study. There is no conflict of interest. This study was supported by the Fondo de Investigaciones Sanitarias (2004-06) Ministry of Health and Consumption, Spain, grant number P1041210.

References

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cal practice: a study of its impact on epilepsy patients’ care. Qual Life Res. 1997;6:629. 42. Rebollo P, Bobes J, González MP, Saíz P, Ortega F. Factores asociados la calidad de vida relacionada con la salud (CVRS) de los pacientes con terapia renal sustitutiva (TRS). Nefrología. 2000;20:171. 43. Velikova G, Booth L, Smith AB, et al. Measuring quality of life in routine oncology practice improves communication and patient well-being: a randomized controlled trial. J Clin Oncol. 2004;22:714. 44. Espallargas M, Valderas J, Alonso J. Provision of feedback on perceived health status to health care professionals: a systematic review of its impact. Med Care. 2000;38:175. 45. Clancy CM, Eisenberg JM. Outcomes research: measuring the end results of health care. Science. 1998;282:245. 46. Giacoletto SG, Bujaldón de Martín MI. Aspectos psicológicos de los enfermos en técnicas sustitutivas de la función renal, de sus familiares y del equipo tratante. Nefrología Clínica 2ª Ed. Madrid: Editorial Panamericana; 2003:805. 47. Liem YS, Bosch JL, Arends LR, Heijenbrok-Kal MH, Hunink MG. Quality of life assessed with the Medical Outcomes Study Short Form 36-Item Health Survey of patients on renal replacement therapy: a systematic review and meta-analysis. Value Health. 2007;10:390-7. 48. Garrat A, Schmidt L, Mackintosh A, Fitzpatrik R. Quality of life measurement bibliographic study of patient assessed health outcome measures. BMJ. 2002;324:1417. 49. Vilagut G, Ferrer M, Rajmil L, et al. El cuestionario de salud SF-36 español: una década de experiencia y nuevos desarrollos. Gaceta Sanitaria. 2005;19:135. 50. Isla Pera P, Moncho Vasallo J, Insa Soria R, Torras Rabasa A. Calidad de vida en los enfermos trasplantados de ríñón y páncreas. Libro de Ponencias del X Encuentro Internacional de Investigación en Enfermería Madrid: Instituto de Salud Carlos III; 2006. p. 126-27. ISBN 84-690-2248-2. 51. Niu SF, Li IC. Quality of life of patients having renal replacement therapy. J Adv Nurs. 2005;51:15. 52. Cameron JL, Whiteside C, Katz J, Devins GM. Differences in quality of life across renal replacement therapies: A meta-analytic comparison. Am J Kidney Dis. 2000;35:629. 53. Bunnapradist S, Cho YW, Cecka JM, Wilkinson A, Danovitch GM. Kidney allograft and patient survival in type I diabetic recipients of cadaveric kidney alone versus simultaneous pancreas kidney transplants: a multivariate analysis of the UNOS database. J Am Soc Nephrol. 2003;14:208. 54. Dew MA, Switzer GE, Goycoolea JM, et al. Does transplantation produce quality of life benefits? Transplantation. 1997;64:1261. 55. Reddy S, Stablein D, Taranto S, et al. Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Am J Kidney Dis. 2003;41:464. 56. Hakim NS. Recent developments and future prospects in pancreatic transplantation. Exp Clin Transplant. 2003;1:26. 57. Gross CR, Limwattananon C, Matthees BJ. Quality of life after pancreas transplantation: a review. Clin Transplant. 1998; 12:351. 58. Hopt UT, Drognitz O. Pancreas organ transplantation. Short and long-term results in terms of diabetes control. Langenbecks Arch Surg. 2000;385:379. 59. Sureshkumar KK, Patel BM, Markatos A, Nghiem DD, Marcus RJ. Quality of life after organ transplantation in type 1 diabetics with end-stage renal disease. Clin Transplant. 2006;20:19. 60. Orr A, Willis S, Holmes M, Britton P, Orr D. Living with a kidney transplant: a qualitative investigation of quality of life. J Health Psychol. 2007;12:653. 61. Matas AJ, Halbert RJ, Barr ML, et al. Life satisfaction and adverse effects in renal transplant recipients: a longitudinal analysis. Clin Transplant. 2002;16:113. 62. Mártinez-Castelao A, Górriz JL, García-López F, López-Revuelta K, De Alvaro F, Cruzado JM. Perceived health-related quality of life and comorbidity in diabetic patients starting dialysis (CALVIDIA study) J Nephrol. 2004;17;544. 63. Gorlén T, Ekeberg O, Abdelnoor M, Enger E, Aarseth HP. Quality of life after kidney transplantation: a 10-22 years follow-up. Scand J Urol Nephrol. 1993;27:89. 64. Badía X, Alonso J, Brosa M, Lock P. Reliability of the Spanish version of the Nottingham Health profile in patients with stable end-stage renal disease. Soc Sci Med. 1994;38:153.

65. Álvarez-Ude F, Vicente E, Badía X. La medida de la calidad de vida relacionada con la salud en los pacientes en programa de hemodiálisis y diálisis peritoneal continua ambulatoria de Segovia. Nefrología. 1995;15:572. 66. Dew MA, Kormos RL, DiMartini AF, et al. Prevalence and risk of depression and anxiety-related disorders during the first three years after heart transplantation. Psychosomatics. 2001;42:300. 67. Dew MA, Kormos RL, Winowich S, Stanford E, Carroza L, Griffith BP. Long-term posttransplant quality of life outcomes in patients bridged to transplant with ventricular assist devices. J Heart Lung Transplant. 2001;20:203. 68. Dew MA, Myaskovsky L, Switzer GE, DiMartini AF, Schulberg HC, Kormos RL. Profiles and predictors of the course of heart transplantation. Psychol Med. 2005;35:1215. 69. Horina JH, Holzer H, Reisinger EC, Krejs GJ, Neugebauer JS. Elderly patients and chronic hemodialysis. Lancet. 1992; 339:183. 70. Watanabe T, Hiraga S. Psychiatric symptoms during the week after renal transplantation. Transplant Proc. 1999;31:251. 71. Cardoso G, Arruda A. As representaçôes sociais da soropositividade entre as mulheres e a adesâo ao tratamento. Cadernos Saúde Coletiva. Rio de Janeiro: UFRJ/NESC 2003;11:183. 72. Hader SL, Smith DK, Moore JS, Holmberg SD. HIV infection in women in the United States: status at the Millennium. JAMA. 2001;285:1186. 73. Valderrábano F, Jofre R, López-Gómez JM. Quality of life in endstage renal disease patients. Am J Kidney Dis. 2001;38:443. 74. Moore KA, Burrows GD, Hardy KJ. Anxiety in chronic liver disease: Changes posttransplantation. Stress Med. 1997;13:49. 75. Ichikawa Y, Fujisawa M, Hirose E, et al. Quality of life in kidney transplant patients. Transplant Proc. 2000;32:1815. 76. Caccamo L, Azara V, Doglia M, et al. Longitudinal prospective measurement of the quality of life before and after liver transplantation among adults. Transplant Proc. 2001;33:1880-1. 77. Pérez-San-Gregorio MA, Martín-Rodríguez A, Díaz-Domínguez R, Pérez-Bernal J. The influence of posttransplant anxiety on the long-term health of patients. Transplant Proc. 2006;38:2406. 78. Ponton P, Rupolo GP, Marchini F, et al. Quality-of-life change after kidney transplantation. Transplant Proc. 2001;33:1887. 79. Sesso R, Rodríguez-Neto JF, Feraz MB. Impact of socioeconomic status on the quality of life of ESRD patients. Am J Kidney Dis. 2003;41:186. 80. Kwiatkowski A, Michalak G, Czerwinski J, et al. Quality of life after simultaneous pancreas-kidney transplantation. Transplant Proc. 2005;37:3558. 81. Langenbach M, Stippel D, Beckurts KT, Geisen J, Kohle K. How do patients experience their body after simultaneous pancreas-kidney transplantation? Z Psychosom Med Psychother. 2004;50:86. 82. Forsberg A, Lorenzon U, Nilsson F, Backmana L. Pain and health related quality of life after heart, kidney, and liver transplantation. Clin Transplant. 1999;13:453. 83. Kreitzer MJ, Gross CR, Ye K, Rusas V, Treesak V. Longitudinal impact of mindfulness meditation on illness burden in solidorgan transplant recipients. Prog Transplant. 2005;15:166. 84. Wainwright SP, Fallon M, Gould D. Psychosocial recovery from adult kidney transplantation: a literature review. J Clin Nurs. 1999;8:233. 85. Soto M, Failde I. La calidad de vida relacionada con la salud como medida de resultados en pacientes con cardiopatía isquémica. Rev Soc Esp Dolor. 2004;11:53. 86. Kaplan G, Camacho T. Perceived health and mortality: a nineyear follow-up of a human population laboratory cohort. Am J Epidemiol. 1983;117:292.  87. Ifudu O, Paul HR. Effect of missed hemodialysis treatments on mortality in patients with end-stage renal disease. Nephron. 1998;79:385. 88. Kutner NG, Lin LS, Fielding B, Brogan D, Hall WD. Continued survival of older hemodialysis patients: investigation of psychosocial predictors. Am J Kidney Dis. 1994;24:42. 89. Parkerson GR, Gutman RA. Perceived mental health and disablement of primary care and end-stage renal disease patients. Int J Psych Med. 1997;27:33. 90. Frank W. The wounded storyteller: body, illness and ethics. Chicago: University of Chicago Press; 1995. 91. Permanyer-Miralda G, Brotons C. Determinación de la calidad de vida en los pacientes con coronariopatía: el estado de la cuestión. Cardiovascular Risk Factors. 1999;8:17-26.

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Trends in Transplant. Transplantation 2008;2:78-91 2008;2

Adult Liver Transplantation in HIV-1 Infected Patients Fernando Agüero1, Montserrat Laguno1, Montserrat Tuset2, Carlos Cervera1, Asunción Moreno1, Juan-Carlos García-Valdecasas3, Antonio Rimola4, José M. Miró1, and the Hospital Clinic OLT in HIV Working Group 1 Infectious Diseases Service; 2Pharmacy Department; 3Liver Surgery Unit; 4Liver Unit CIBEREHD; Hospital Clinic – IDIBAPS, University of Barcelona, Barcelona, Spain

The members of the Hospital Clinic OLT in HIV Working Group are: J.M. Miró, A. Rimola, A. Moreno, M. Laguno, M. Larrousse, J.L. Blan­co, J. Mallolas, C. Cervera, M. Tuset, M. Monras, N. Freixa, J. Blanch, C. Lanaspa, E. de Lazzari, J.C. García-Valdecasas, J.M. Gatell (Hospital Clinic – IDIBAPS. University of Barcelona, Barcelona); C. Tural and D. Fuster (Hospital Germans Trías i Pujol, Badalona, Barcelona, Spain); and J. Murillas and E. Moitinho (Hospital Son Dureta, Palma de Mallorca, Spain).

Abstract The prognosis of HIV infection has dramatically improved in recent years with the introduction of combined antiretroviral therapy. Currently, liver disease is one of the most important causes of morbidity and mortality, even more so given the high rate of hepatitis C virus coinfection in countries where drug abuse has been an important HIV risk factor. Survival of HIV-coinfected patients with end-stage liver disease is poor and shorter than that of the non HIV-infected population. One-year survival of HIV-infected patients with end-stage liver disease is only around 50-55%. Infection with HIV is no longer a contraindication to transplantation, which is becoming a standard therapy in most developed countries. The HIV criteria used to select HIV-infected patients for liver transplantation are quite similar in Europe and North America. Current criteria state that having had an opportunistic infection (e.g. tuberculosis, candidiasis, Pneumocystis jiroveci pneumonia) is not a strict exclusion criterion. However, patients must have a CD4 count above 100 cells/mm3 and a plasma HIV-1 RNA viral load which is suppressible with antiretroviral treatment. More than 300 orthotopic liver transplants in HIV-infected patients have been published in recent years and the mid-term (three-year) survival was similar to that of HIV-negative patients. The main problems in the posttransplant period are the pharmacokinetic and pharmacodynamic interactions between antiretroviral and immunosuppressive agents and the recurrence of HCV infection, which is the principal cause of posttransplant mortality. There are controversial results regarding midterm survival of HIV/HCV-coinfected patients in comparison with HCV-monoinfected ones. However, one study showed a trend of poorer five-year survival of HIV/HCV-coinfected patients. There is little experience with the treatment of recurrent HCV infection. Preliminary studies showed rates of sustained virologic response ranging between 15-20% in HIV/HCVcoinfected recipients. Liver transplantation in HIV/HBV-coinfected patients had a good prognosis because HBV recurrence can be successfully prevented using immunoglobulins and anti-HBV drugs. Finally, this field is evolving continuously and the indications for liver transplantation or the management of HCV coinfection may change in the future as more evidence becomes available. (Trends in Transplant. 2008;2:78-91) Corresponding author: José M. Miró, [email protected] Correspondence to: José M. Miró Servicio de Enfermedades Infecciosas Hospital Clínic – IDIBAPS Villarroel, 170 08036 Barcelona, Spain E-mail: [email protected]

78

Fernando Agüero, et al.: Adult Liver Transplantation in HIV-1 Infected Patients

Key words End-stage liver disease (ESLD). HIV-1-infection. Hepatitis C virus infection. Hepatitis B virus infection. MELD score. Child-Turcotte-Pugh classification. Liver transplantation. Mortality. Prognosis.

Introduction The rate of HIV-related mortality has declined dramatically since 1996 in Europe and the USA with the widespread use of combined antiretroviral therapy (cART). Conversely, end-stage liver disease (ESLD), mainly caused by hepatitis C virus (HCV), is becoming an important cause of death among human immunodeficiency virus-1 (HIV-1)-infected patients1-4. Or­tho­topic liver transplantation (OLT) is the only therapeutic option for patients with ESLD5,6. Ho­wever, until a few years ago, infection with HIV was an absolute contraindication to any type of transplantation. The prognosis and the fear that transplant-associated immunosuppres­sion could speed up the progression to AIDS or increase the risk of opportunistic infections meant that OLT was ruled out7. The spectacular improvement in prognosis observed in HIV-infected patients after the introduction of cART in 1996 has meant that transplantation has now been reconsidered in patients with ESLD. The main objective of this paper is to define the criteria to select HIV-infected patients for OLT, taking into account that this field is evolving continuously and the indications for OLT or ma­ nagement of these patients may change as more evidence becomes available.

Experience of orthotopic liver transplantation in HIV infected patients in the combined antiretroviral therapy period (1996-2006) Initial attempts at OLT in HIV-infected pa­ tients before the introduction of cART re­gi­mens (before 1996) provided very poor results. Putting together the most important case series pub-

lished8-10, three-year survival was on­ly 44%. Most patients died because of HIV-disease progression, with graft function being normal in many cases. However, since the in­troduction of cART in 1996, HIV-infected reci­pients of liver transplants have improved their short- and midterm survival. Accumulated ex­perience in North America and Europe in the last 10 years has shown that more than 300 OLT cases were performed11-20 (Table 1). Survi­val was greater than 70% in most series with dif­ferent periods of follow-up. In more than two-thirds of cases, the primary indication for OLT was HCV coinfection. Although cases ca­me from different institutions, the criteria used for liver transplantation were quite similar. In ge­neral, candidates did not have a prior histo­ry of opportunistic infections, and had CD4 counts > 100 cells/µl and undetectable plasma HIV RNA on cART (or available drugs for successful treatment in the post-OLT period)14,21. In a multicentre and multinational retrospective study performed by Ragni, et al., including 23 HIV-infected patients who underwent OLT, sur­ vival at three years was 73 and 79% (p = NS) for HIV-infected and non HIV-infected recipients, respectively12. Similar ra­tes were seen for graft survival. In all cases published in the cART era, the main cause of death was due to hepatitis C recurrence. In any case, three-year survival in HIV-infected re­cipients in the cART period was almost 30% higher than in the pre-HAART era8-10 and the­refore, at present, HIV infection is no longer a formal contraindication to transplantation. Ho­we­ver, de Ve­ra, et al.17 recently published one single-center series of HIV/HCV-coinfected pa­tients with the longest mean follow-up (27 ± 5 months). They did a case-control study com­pa­ring the evolution of 27 HIV/HCV-coin79

Trends in Transplantation 2008;2

Table 1. Liver transplantation in HIV-infected patients: main series of cases (≥ 10) in the late combined antiretroviral therapy era (2002-2008) Author

Year

Country

No. cases

Virus

Follow-up (months)

Survival rate

Roland, et al.11

2002

Internacional

19

Most HCV

10

15 (79%)

Ragni, et al.12

2003

Internacional

24

HCV 62% HBV 29%

17

18 (75%)

Neff, et al.13

2003

USA

16

HCV or HBV

12

14 (87%)

Fung, et al.14

2004

USA

29

HCV 90%

18

20 (69%)

Norris, et al.

2004

U.K.

14

HCV 50% HBV/OH 50%

12 19

2 (29%) 7 (100%)

Duclos-Vallée, et al.16

2006

France

41

HCV 88% HBV 12%

18

29 (81%) 5 (100%)

De Vera, et al.17

2006

USA

27

HCV 100%

27

13 (48%)

Schereibman, et al.18

2007

USA

15

HCV 40% HBV 33%

74

10 (67%)

Coffin, et al.19

2007

USA

16

HBV 100%

8,5

14(86%)

Spanish study*

2008

Spain

127

HCV 94%

21

89(74%)

Grossi, et al.

2008

Italy

60

HCV 65% HBV 12%

12

41(58.3%)

15

20

*Unpublished data.

fected patients with 54 HCV-monoinfected patients (control group) who underwent OLT. Five-year survival was poorer in coinfected pa­tients (33 vs. 72%), although this difference was not statistically significant (p = 0.07). In a recent retrospec­tive study carried out in the USA that enrolled 138 HIV-infected patients with liver transplant in the cART era (1996-2006), the rate of survival at two and three years was significantly lower in the patients with HIV infection (70 and 60%) than in the ge­neral population (81 and 77%; n = 30,520), although this difference was observed in the HCV/HIV and HBV/ HIV-coinfected group exclusively. None of the 24 trans­planted HIV-mo­no­infected patients died. The­re­fore, liver transplantation in HIV-infected patients does not have a higher short-term mor­ tality (1-2 years). Nevertheless, the mana­gement and outco­me of HCV reinfection could affect the survival in the medium (3-5 years) and long term (5-7 years)22. In France, Duclos-Vallee, et al. analy­zed the data of 35 HIV/HCV-coinfected patients and 80

compared them with 44 HCV-mo­no­infected patients. The rates of survival at two and five years were 81 and 91% in HIV/HCV-co­infected patients and 51 and 73% in HCV-monoinfected patients, respectively (p = 0.004)23. Conversely, in a Spanish multicentre ca­secontrol study24, the survival rate of patients and grafts at three years was similar in HIV/HCVcoinfected patients (n = 51) to that in HCV-monoinfected patients (n = 1,177). The sur­vival rates at one, two, and three years we­re 88 versus 81%, 75 versus 74%, and 64 ver­sus 69%, respectively (p = NS). Although there are no available data at five years in this Spanish study, the differences observed between the Spanish results and the French and American ones show the real need to implement multicentre studies with high number of cases, which may allow examining the different factors that could have an influence in the long-term prognosis of this procedure and to explain these differences. Variables li­ke donor and recipient characteristics, viral ki­netic of both viruses, and the efficacy and sa­fety of antiviral

Fernando Agüero, et al.: Adult Liver Transplantation in HIV-1 Infected Patients

Table 2. HIV criteria for orthotopic liver transplantation in some European countries and the USA Spain30

Italy34

UK29

USA35

Some*

None in the previous year.

None after HAART-induced immunological reconstitution.

Some†

> 200 or > 100 if decompensated cirrhosis

> 200 or > 100 if portal hypertension

> 100‡

Yes

Yes

Previous C events: Opportunistic infections Neoplasms CD4 cell count/mm3 Plasma HIV-1 RNA viral load BDL on HAART§

No > 100‡ Yes

No

No

Yes

BDL: Below detections levels (< 200 copies/ml). *In Spain, patients with previous tuberculosis, Pneumocystis jiroveci pneumonia (PCP) or esophageal candidiasis can be evaluated for OLT. † In USA, PCP and esophageal candidiasis were not exclusión criteria. ‡ Patients with previous opportunistic infections should have > 200 CD4 cells/mm3. §If PVL was detectable, post-OLT suppression with combined antiretroviral therapy should be predicted in all patients.

therapy could have an impact on the outcome of these patients and, the­refore, they must be analyzed.

and 7,000 HBV-coinfected patients among a total number of 140,000 HIV-infected patients.

In Spain, the OLT program in HIV-infec­ted patients, started in January 2002 (GESIDA unpublished data), has performed 127 liver transplants in 122 patients up to March 2008. More than 95% of patients were HCV/HIVcoinfected. There were 33 deaths (26%) after a median follow-up of 21 months.

Using the same calculations, the potential number of candidates to be evaluated for liver transplantation would be around 1,142 cases.

Magnitude of end-stage liver disease in Europe and the USA According to current estimates, there are around 540,000 HIV-infected patients in Wes­tern European countries25. The prevalence of HCV and HBV coinfection in European HIV-infected patients was 33 and 9%, respectively26,27. Thus, the estima­ted number of HCV-and HBV-coinfected patients is around 180,000 and 49,000 cases, res­pectively. In a cross-sectional study performed in Spain28, 8% of coinfected patients had clinical or histological criteria of cirrhosis and 17% of them met the Spanish criteria to be admitted in an OLT waiting list. Therefore, the potential number of candidates for OLT in Europe would be around 3,100 cases. According to these studies 25,28, in Spain there are 77,000 HCV-coinfected individuals

Criteria for including HIV-infected patients in the liver transplant waiting list Liver disease criteria Criteria concerning the liver disease are the same as for the non HIV-infected population, the main indication for OLT in HIV-infec­ted patients being ESLD caused by HCV coinfection. Less frequent indications were HBV coinfection (either acute or ESLD) and liver can­cer. The British HIV Association, with the UK and Ireland Liver Transplantation Center, has recently published a Consensus Guideline reviewing the liver disease criteria as well as the HIV-infection criteria29. In this guide, indications for liver transplantation include acute liver failure, decompensated liver disease (with ascites, encephalopathy [it is important to exclude HIV-related dementia], or variceal bleeding difficult to ma­na­ge with standard therapies, and poor liver function [e.g. albumin < 30 g/l, INR > 41.5 and elevated serum 81

Trends in Transplantation 2008;2

bilirubin > 450 mmol/l]) and hepatocellular carcinoma (HCC) detected du­ring regular tumor surveillance. Criteria for liver transplantation in patients with HCC are: no more than three tumor nodules, no nodule must be > 5 cm in diameter, absence of macroscopic portal vein invasion, and absence of recognizable extrahepatic disease29.

HIV-infection criteria in Spain In Spain, a multidisciplinary Task For­ce30 has defined the following clinical, immunologic, and virologic criteria.

Clinical criteria Ideally, patients should not have suffered previously from AIDS-defining diseases, as they may have a greater risk of reactivation. However, the improved prognosis post-cART means that some authors are in favor of withdrawing exclusion criteria for some opportunistic infections which can be efficacious­ly treated and prevented, such as tuberculosis, candidiasis, and Pneumocystis jirovecii pneumonia21,31-33. The Spanish Task Force considered that the experience with other HIV-related opportunistic infections and tumors (e.g. Kaposi sarcoma) is still too limited to make any recommendations.

Immunologic criteria All groups have agreed that the CD4+ lymphocyte count should be > 100 cells/mm3 for OLT34,35. This figure is lower than that used for kid­ ney transplantation (i.e. CD4 > 200 cells/mm3) because patients with cirrhosis often have lym­ pho­penia due to hypersplenism, which leads to a lower absolute CD4+ count, despite high CD4 percentages and good virologic control of HIV.

Virologic criteria The essential criterion for OLT is that the patient must be able to have effective and long-lasting antiretroviral therapy during the 82

posttransplant period30. The ideal situation is one in which the patient tolerates cART before transplantation and is ready for the transplant with undetectable plasma HIV viral load by ul­ trasensitive techniques (< 50 copies/ml). Ne­ vertheless, this is not always possible for seve­ ral reasons: 1. In some patients with ESLD it may be difficult to maintain an undetectable HIV viral load in plasma because they often experience intolerance or to­xicity related to antiretroviral drugs, which must then be stopped. In these cases, and to avoid resistance, it is better to save antiretroviral therapy for the posttransplant period. 2. Some patients remain viremic with cART. In these cases, it is mandatory to carry out antiretroviral sensitivity testing (genotypic or phenoty­pic resistance testing)36 to ascertain the real therapeutic options. The eva­lua­ting team and HIV experts will eva­luate whether the patient has effective and durable rescue therapy. 3. Some patients do not have an indication for cART as they are long-term non­progressors or do not have immunologic criteria (CD4+ lymphocyte count > 350 cells/mm3) or clinical criteria to start cART and, therefore, they have viremia that is detectable in plasma. In this setting, it is unknown whether and when (pretransplant or posttransplant) it would be beneficial to initiate cART in order to reach an undetectable HIV viral load in plasma.

Other criteria Furthermore, to include an HIV-infected patient on the OLT waiting list, the candidate must have a favorable psychiatric evaluation. Patients who actively consume drugs will be ex­ cluded. In Spain, it is recommended that there be a consumption-free period of two years for heroin and cocaine30 and six months without addiction for other drugs (e.g. alcohol). Patients who are on stable methadone main­tenance programs are not excluded from transplantation and can continue on such programs after the transplant37.

Fernando Agüero, et al.: Adult Liver Transplantation in HIV-1 Infected Patients

Finally, as is the case with any transplant candidate, HIV-infected patients must show an appropriate degree of social stability to ensure an adequate care in the posttransplant period.

HIV criteria in other European and North America countries Most liver transplant groups from Europe and North America are using similar HIV cri­teria, which are summarized in table 229,30,34,35. It is important to point out that, currently, to have a previous opportunistic infection is not a strict exclusion criterion by itself. In fact, the NIH-sponsored study has recently updated the inclusion criteria for opportunistic compli­ca­tions38 and only those diseases without therapy remain exclusion criteria for liver trans­plantation (e.g. progressive multifocal leukoencephalopathy, chronic cryptosporidiosis, mul­tidrug-resistant systemic fungal infections, primary central nervous system lymphoma, and visceral Kaposi’s sarcoma). On the other hand, a CD4 cell count > 200 cells/mm3 is the cutoff used in Italy34 and the UK29, unless patients had decompensated cirrhosis or portal hypertension, respectively. In these scenarios, they use the same CD4 cell threshold used in Spain and the USA (e.g. 100 cells/mm3)30,35.

Special considerations in HIV-infected patients Orthotopic liver transplantation in HIV-infected patients is a complex scenario that requires a multidisciplinary approach6,21. Sites wishing to carry out transplants in HIV-positive patients must have a multidisciplinary team that can periodically evaluate these patients du­ring the pre- and posttransplant periods. The team should include members from the liver transplant team (medical and surgical), in­fectious diseases and HIV specialists, a psy­cho­logist/psychiatrist, an expert on alcoholism and drug abuse, and a social worker.

Controversial issues in the pretransplant period Waiting list mortality in HIV-infected patients with ESLD is very high. This is because survival of

HIV-infected patients with decompensated cirrhosis is much lower than in HIV-ne­gative patients39-41. Pineda, et al.40 have re­­cently shown in a multicentre case-control study performed in Andalusia (Spain) that the outcome of cirrhosis after the first decompensation in HIV/HCV-coinfected patients is much worse than in the HCVmonoinfected population. Survival at one, two, and five years for co­infected and monoinfected populations was 54/74%, 40/61% and 25/44%, respectively. In another study41, the same group of investigators identified as independent predictors of a poor outcome in HIV/HCV-coinfected patients the severity of liver disease (Child-Turcot­tePugh [CTP] classification or developing hepatic encephalopathy as the first hepatic decompensation) and the level of cellular im­munosuppression (< 100 CD4 cells/mm3). On the other hand, HAART was associated with a reduced mortality. Another Spanish study has followed the evolution of 104 HIV-infected patients with cirrhosis after their first hepatic decompensation or HCC39. Median survival time of this cohort was 14 months, similar to the Merchante’s co­hort (13 months)40. This study included HCV-infected and non HCV-infected patients and we did not find significant differences in survival according to the etiology of cirrhosis, sug­gesting that HIVinfected patients have an overall poor outcome regardless of the nature of their liver disease. Furthermore, the model for end-stage liver disease (MELD) score was the only factor independently associated with mortality. This is of relevance because during the last years MELD has been increasingly used to establish the prognosis of patients with cirrhosis and, consequently, to indicate liver transplantation. Once the HIV-infected patient with ESLD is included in the transplant waiting list, mortality of HIV-infected patients remained very high (> 60%). This occurred mainly because, in most Spanish centers, prioritization for organ allocation was predominantly established on the basis of the time in the waiting list. In comparison, the annual mortality rate for non HIV-1-infected patients while on the liver trans­plant waiting list in 83

Trends in Transplantation 2008;2

our center ranged between 8-12% in recent years. High mortality rates of HIV/HCV-infected patients with ESLD waiting for liver transplantation have been previously re­ported in two studies42,43. In one of these stu­dies43, mortality rates during pretransplant evaluation among HIV-positive (n = 58) and HIV-negative (n = 1,359) patients were 36 and 15%, respectively (p < 0.001). Nevertheless, these data have not been verified in a recent U.S. multicentre study. Mor­tality in the waiting list was 14% in patients with HIV infection (n = 167) and 11% in the con­trol group (n = 792) (p = 0.30). In the mul­tivariate analysis, a MELD score higher than 25 was the only variable related to death in the waiting list44. In any case, physicians attending cirrhotic HIV-infected patients should prospectively follow these patients and they should evaluate them early for OLT after the first clinical decompensation of the liver disease: ascites, hepatic encephalopathy, spontaneous bac­terial peritonitis, gastroesophageal variceal bleeding and/or jaundice. Similarly, patients whose cirrhosis is associated with HCC should also be evaluated. Both prevention and effective treatment of these complications may improve the likelihood of patient survival until OLT45-48. Regarding the antiretroviral therapy, the­se patients should follow the general recom­men­ dations49,50 and their liver function must be clo­sely monitored in order to detect he­patotoxicity. Furthermore, some antiretroviral drugs may be contraindicated in cirrhotic patients (e.g. dida­nosine, nevirapine, full-dose ri­tonavir) and their dosing should be adjusted according to the degree of hepatic impairment51-53. Therapeutic drug monitoring may be useful for efavirenz and protease inhibitors. Indinavir and atazanavir can increase un­­conju­ga­ted bilirubin levels by inhibiting UDP-glucuronosyltransferase. As total bilirubin is a component of both CTP and MELD scores, their results in patients taking the­se drugs should be interpreted cautiously. On the other hand, organ transplantation in HIV-infected patients has raised ethical problems, which have not yet been completely re84

solved. However, currently most groups agree that HIV-infected patients should recei­ve the same treatment as other patients and be included on waiting lists under the same conditions54. The pretransplant evaluation of donors and recipients should be the same as for non HIV-infected patients. With respect to the type of donor to be used in HIV-infected patients, most solid organ transplants were carried out using cadaveric donors. In recent years, and as a consequence of the increased demand for organs, the number of living donors has in­creased. Nevertheless, the benefits of this technique have yet to be demonstrated in the HIV-infected population.

Issues to consider in the posttransplant period After OLT, patients and physicians start a new and complex clinical situation. Patients must receive a large quantity of medication and this can compromise adherence. In addition to cART, which they may be accustomed to, they must take immunosuppressive drugs and the habitual prophylaxis against opportunistic infections and other medications to ma­na­ge complications that frequently develop after OLT (e.g. diabetes, hypertension). Patients on methadone programs must continue with this. The HCV-coinfected patients may re­quire therapy with interferon and ribavirin.In this new scenario several issues must be considered such as, the course of HIV infection, immune suppression and allograft rejection, pharmacological interactions among the different type of drugs used and the course of HCV and HBV infection recurrence. Patients usually follow the same cART re­gimens that they took during the pre-OLT pe­riod, but these regimens can be changed in the post-OLT period on an individual basis in order to choose the easiest regimen to adhere to, with lower potential for pharmacolo­gic interactions with immunosuppressive agents and anti-HCV drugs, and lower liver toxicity. In any case, we should follow the general re­com­mendations for antiretroviral therapy in adults49,50, and liver function must be closely monitored in order to

Fernando Agüero, et al.: Adult Liver Transplantation in HIV-1 Infected Patients

detect hepatotoxicity. Furthermore, HIV-infected patients require adequate support during all the post-transplant timeline and they must understand the importance of a correct adherence to all their treatment schedules. There are solid data showing that HIVinfected patients do not have an increased risk of postoperative complications or a higher incidence of opportunistic infections or tumors than HIV-negative patients6,55,56. The CD4 cell counts and plasma HIV viral loads remain stable and undetectable, respectively, as long as cART can be administered. Further­mo­re, immunosuppressive drugs (e.g. calcineurin inhibitors, mycophenolic acid, prednisone) can reduce HIV replication in two ways: first, by reducing the immune activation indu­ced by HIV; and, second, because calci­neurin inhibitors and mycophenolic acid have direct anti-HIV activity14,21. Furthermore, mycopheno­lic acid enhances abacavir action against HIV57.

Immunosuppression and rejection issues There are no specific immunosuppressive regimens for HIV-infected patients, and each centre uses the same regimens as for HIV-negative patients. As mentioned previous­ly, the use of standard immunosuppressive the­rapy in patients with well-controlled HIV-in­fection did not increase their susceptibility to op­portunistic infections or malignant conditions6,55,56. Therefore, HIV-infected patients should follow the same prophylaxis protocols as the general population. In some studies, the rates of allograft rejection were higher than in the HIV-negative population. The cause of this phenomenon is unknown, and it is particularly noticeable in kidney transplants, suggesting that HIV does not protect against allograft rejection33,58,59. At present, the best re­gimen of immune suppression in OLT HIV-infected recipients is unknown.

Pharmacologic interactions There are important pharmacologic interactions between antiretrovirals and immu-

nosuppressive or anti-HCV drugs which may be clinically relevant52,53 that are summarized in table 3. Cyclosporine A, tacrolimus, and sirolimus are metabolized in the liver using cytochro­me P450, whereas mycophenolate mofetil un­der­goes glucuronization in the liver. Antiretrovirals can act as inhibitors or inducers of the­se enzymatic systems. When they act as en­zyme in­hibitors (e.g. protease inhibitors [PI]), they in­crease concentrations of these immunosuppressants and can lead to toxicity. For this rea­son, doses must be markedly reduced (e.g. tacrolimus 1 mg/ week in patients taking Ka­letra®)60-62. These interactions have caused some episodes of acute rejection in patients who stopped PI while taking calcineurin inhi­bitors. On the other hand, when antiretrovirals act as enzyme inducers (e.g. nonnucleoside re­verse transcriptase inhibitors [NNRTI]), they reduce drug levels and can trigger rejection, and therefore doses of most immunosuppressive drugs must be increased63. Therefore, it is important to know very well the possible drug in­teractions and closely monitor the levels of im­munosuppressive drugs. In addition, there are important overlapping acute and chronic to­xicities between antiretroviral and immunosuppressive drugs that should be taken into account (e.g. liver, renal and/or bone marrow toxicities, hyperlipidemia, diabetes, osteoporosis)49-50. As a consequence of these important interactions between some antiretroviral families (i.e. NNRTI or PI) and immunosuppressive drugs, some researchers are using enfuvirtide plus two nucleoside reverse transcriptase inhibitors (NRTI) in order to avoid these interactions64. It is important to highlight that the introduction of new families of antiretrovirals with safer profiles of interactions could be very useful in the future. Raltegravir, an HIV-1 integrase inhibitor, could be an example of this because it does not share routes of metabolization with any of the commonly used immunosuppressors drugs, and therefore it would not be necessary to modify its dosification. Although sporadic cases of the use of this drug in this setting have been published65, more infor85

Trends in Transplantation 2008;2

Table 3. Drug interactions between antiretroviral agents and immunosuppressive drugs Drug

Mycophenolate mofetil

Cyclosporin A

Sirolimus

Tacrolimus

Abacavir

Both abacavir and MMF are eliminated mainly by glucuronidation. However, clinically important drug-drug interactions have not been reported.

Amprenavir

Theoretically, based on the elimination pathways, a pharmacokinetic drugdrug interaction is unlikely.

Didanosine

Theoretically, based on the elimination pathways, a pharmacokinetic drug-drug interaction is unlikely.

Efavirenz

Theoretically, based on the elimination pathways, a pharmacokinetic drugdrug interaction is unlikely.

Minimal interactions with EFV and CsA or TAC are expected. Some patients needed an initial CsA dose of 350-450 mg b.i.d. followed by a maintenance dose of 250-400 mg b.i.d. TDM of CsA, SRL and TAC is recommended.

Indinavir

Theoretically, based on the elimination pathways, a pharmacokinetic drugdrug interaction is unlikely.

Risk of increased drug levels/toxicity of immunosuppressive drugs. Markedly lower doses of CsA and TAC may be required. Some patients needed an initial CsA dose of 75-100 mg b.i.d., followed by a maintenance dose of 75 mg b.i.d. TDM of CsA, SRL and TAC is recommended.*

Lamivudine

Theoretically, based on the elimination pathways, a pharmacokinetic drug-drug interaction is unlikely. However, as lamivudine is primarily renally excreted, nephrotoxic drugs could impair its elimination.

Lopinavir/ ritonavir

Theoretically, MMF glucuronidation could be increased (and blood levels reduced) by RTV.

Risk of increased drug levels/toxicity of immunosuppressive drugs. Markedly lower doses of CsA may be required. Some patients needed an initial dose of 25 mg b.i.d of CsA. Patients on LPV/r + TAC may need a dose reduction to 1 mg once weekly or even less. When LPV/r is initiated in a patient on TAC, the next TAC dose may need to be delayed for between 3-5 weeks, depending on hepatic function. TDM of CsA, SRL and TAC is recommended.*

Nelfinavir

Theoretically, MMF glucuronidation could be increased (and blood levels reduced) by NFV.

Risk of increased drug levels/toxicity of immunosuppressive drugs. Markedly lower doses of CsA, TAC and SRL† may be required. Some patients needed an initial dose of 50-75 mg b.i.d of CsA, followed by a maintenance dose of 25 mg b.i.d. Some patients on TAC + NFV required a 40 to 70 fold dose-reduction (to 0.5 mg q.d. or even less). TDM of CsA, SRL and TAC is recommended.*

Nevirapine

Theoretically, based on the elimination pathways, a pharmacokinetic drugdrug interaction is unlikely.

Theoretically, may require increased immunosuppressive drug dosage. Minimal interactions with CsA and NNRTI are expected. Some patients needed an initial dose of 200-250 mg b.i.d of CsA, followed by a maintenance dose of 100-175 mg b.i.d. TDM of CsA, SRL and TAC is recommended.

Ritonavir

Theoretically, MMF glucuronidation could be increased (and blood levels reduced) by RTV.

Risk of increased drug levels/toxicity of immunosuppressive drugs. Markedly lower doses of cyclosporine may be required. TDM of CsA, SRL and TAC is recommended.*

Saquinavir

Theoretically, based on the elimination pathways, a pharmacokinetic drugdrug interaction is unlikely.

Risk of increased drug levels/toxicity of immunosuppressive drugs. Markedly lower doses of CsA may be required. TDM of CsA, SRL and TAC is recommended.*

Stavudine

Theoretically, based on the elimination pathways, a pharmacokinetic drug-drug interaction is unlikely.

Tenofovir

Theoretically, based on the elimination pathways, a pharmacokinetic drugdrug interaction is unlikely.

Zalcitabine

Theoretically, based on the elimination pathways, a pharmacokinetic drug-drug interaction is unlikely.

Zidovudine

Both zidovudine and MMF are eliminated mainly by glucuronidation. However, clinically important drug-drug interactions have not been reported.

Risk of increased drug levels/toxicity of immunosuppressive drugs. Markedly lower doses of immunosuppressive drugs may be required. TDM of CsA, SRL and TAC is recommended.*

Increased risk of nephrotoxicity

Theoretically, based on the elimination pathways, a pharmacokinetic drug-drug interaction is unlikely.

Increased risk of nephrotoxicity

b.i.d: twice daily; CsA: cyclosporin A; EFV: efavirenz; LPV/r: lopinavir/ritonavir; MMF: mycophenolate mofetil; NFV: nelfinavir; q.d.: once daily; SRL: sirolimus; TAC: tacrolimus; RTV: ritonavir; TDM: therapeutic drug monitoring; NNRTI nonnucleoside reverse transcriptase inhibitor. *The antiretroviral is an inhibitor of the P450 isoform CYP3A, which is the primary elimination pathway of CsA, SRL y TAC. Co-administration with the antiretroviral may result in increased plasma concentrations of these immunosuppressive drugs. Patients on protease inhibitors require markedly lower doses of cyclosporine, with continued lowering of the cyclosporine dose over time and ongoing cyclosporine trough monitoring because of progressively increasing cyclosporine bioavailability. †Even with one fifth of the recommended dose of NFV (250 mg/12h), a ninefold increase in sirolimus trough concentration, threefold increase in peak concentration, and 60% increase in the area under the concentration curve 0 to 24 hours has been observed in a liver transplantation patient, compared with patients who were not on NFV.

86

Fernando Agüero, et al.: Adult Liver Transplantation in HIV-1 Infected Patients

mation is needed in order to guarantee a broader use of this an­ti­retroviral drug in this scenario. On the other hand, there also are impor­ tant pharmacodynamic interactions between some NRTI (e.g. didanosine, stavudine and zalcitabine) and ribavirin, a drug used in combination with pegylated interferon to treat HCV infection recurrence in OLT recipients. These interactions have been reviewed in-depth elsewhere66. Finally, given the speed with which new antiretrovirals appear and thus generate unknown interactions, physicians are recommen­ ded to consult updated databases on drug interactions52,53.

gression to fibrosis (≥ F2) was significantly higher in the group of HIV infected patients (p < 0.0001)23. Another U.S. study 17 demonstrated a hig­her rate of cirrhosis at five years in the HIV/ HCV-coinfected population who underwent OLT compared to the HCV-monoinfected population (59 vs. 24%; p = 0.03). These two single-centre studies observed that the survival rate at five years is lower in coinfected patients, as has been reported pre­viously. Finally, a recent study has described two cases of spontaneous clearance of RNA HCV after OLT. This phenomenon is very infrequent and its pathogenic mechanism is not known72.

Course of HCV infection recurrence

Course of HBV infection

After OLT, HCV infection recurrence is universal, regardless of whether the patient is infected by HIV or not. Some studies have sug­ gested that HCV recurrence in coinfected patients tends to be more severe and occurs earlier17,67. Similarly, there is insufficient experience on the efficacy and safety of therapy with interferon and ribavirin in HIV/HCV-coinfected transplant patients. One study6 summarized the reports evaluating the effectiveness of HCV reinfection treatment in OLT with pegylated interferon plus ribavirin. These patients were treated when they had histological criteria. Only 12 (18.5%) out of 65 HCV/HIV-coinfected patients achieved a sustained virologic response14,16,17,68-70 (Table 4).

Replication of HBV is a contraindication for OLT, so only patients without plasma DNA HBV viremia are accepted for OLT. As HBV in­ fection recurrence can be successfully prevented using hepatitis B immunoglobulins and antiHBV drugs (lamivudine, tenofovir, adefovir), the outcome of HBV infection after OLT is much better. Adefovir and tenofovir have pro­ven useful against HBV and could be used in cases of resistance to lamivudine. The HIV-po­sitive patients who require antiretroviral therapy and have a chronic HBV infection can use lamivudine (or emtricitabine) and tenofovir as part of triple antiretroviral therapy73.

New strategies are necessary to impro­ve the outcome of HCV recurrence in this setting. In this regard, a recent German study sho­wed that sustained virologic response was obtained in six out of seven patients treated within the first three months after OLT71. A rapid progression of HCV-related li­ver disease in HIV-infected recipients would represent a major drawback and would lead to a shortened life expectancy of these patients. In fact, currently it is the most important cause of death. A French study observed that the pro-

Probably due to the low incidence of HBV reinfection, the short- and medium-term sur­vival rate in HBV/HIV-coinfected patients is high and similar to that observed in HBV-mo­no­infected patients19,74.

Course of hepatocellular carcinoma It is well known that hepatocellular carcinoma (HCC) has a faster and worse outco­me in HIV/HCV-coinfected people compared with HCV-monoinfected patients75,76. Survival of HCV/HBV-monoinfected patients with HCC detected by screening has im­proved in recent years due to the greater chan­ce of curative 87

Trends in Transplantation 2008;2

Table 4. Summary of the studies evaluating the effectiveness of the treatment of HCV reinfection in orthotopic liver transplantation with pegylated interferon plus ribavirin Author, year of publication

HIV/HCV-coinfected patients

Non-HIV HCV-monoinfected patients (control group)

No. of cases

SVRa No. (%)

No. of cases

SVRa No. (%)

Fung, et al. 200414

12

2 (17%)





Duclos-Vallee, et al. 200616

13

2 (15%)





15

4 (27%)

27

7 (28%)†

Vennarecci, et al. 200668 ‡

 9

0 (0%)





Castells, et al. 200769 #

 5

1 (20%)

9

1 (11%)

Spanish study, 200770

16

4 (25%)





Total

65

12 (18.5%)





de Vera, et al.

200617

*

SVR: sustained virologic response. *Most cases were genotype 1; three patients were treated with classical interferon plus ribavirin. †Rate of sustained virologic response was not specified; data show the rate of virologic response (clearance of HCV RNA from serum). ‡The authors did not specify the type of interferon used. #These patients were included in the Spanish study and were not taken into account for the overall response rate. Miro, et al.6

treatment with the advent of liver transplantation and radiofrequency ablation77. Preliminary Italian experience showed good results in seven HIV-1-infected patients with HCC who underwent OLT. They observed an 86% overall patient and graft survival rate after a mean follow-up period of eight months. They recommend OLT in HIV-infected patients with early stage HCC78,79.

Conclusions All HIV-infected patients with ESLD should be considered as candidates for OLT if they meet the HIV inclusion criteria stated here. The­re is increasing experience with OLT in HIV-infec­ted patients and current data show that short- and mid-term survival is the same as that of HIVnegative patients. The HIV infection can be easily controlled with antiretroviral therapy during the posttransplant period. The evaluation and the pre- and post-OLT ma­nagement of this complex scenario should in­clude an interdisciplinary team composed of members of the OLT team (hepatologists and surgeons), infectious diseases and HIV specialists, psychologists, social workers 88

and mem­­bers of alcohol and other drug detoxification programs. Interac­tions between immunosuppressive agents and antiretrovirals, especially PI and, to a lesser ex­tent, NNRTI, are im­portant and require close monitoring of immunosuppressor plasma levels. Patients do not have a greater risk of opportunistic infections or tumors, and therefore should follow the same prophylaxis protocols as the non HIV-infected population. In patients receiving OLT for HCV cirrhosis, recurrence of the HCV infection is universal during the posttransplant period and it is the main concern. It is unknown whether this reinfection has a worse out­come than in HIV-negative patients and the­re is insufficient experience with pegylated interferon and ribavirin in this population. Ho­we­ver, preliminary data showed low rates of cure (around 20%). The outcome of patients who have received a transplant due to HBV cirrhosis seems to be much better since there is an efficacious prophylaxis against recurren­ce (HBV-specific immunoglobulin and anti-HBV drugs).

Future research needs There are several issues that should be explored in the future:

Fernando Agüero, et al.: Adult Liver Transplantation in HIV-1 Infected Patients

1.  Since survival is much shorter in HIVcoinfected patients, strategies to ma­ke OLT available sooner after patient assignment to this procedure should be underlined. 2.  Currently, there are many sites with active OLT programs in HIV-infected patients, but the number of cases is too small in each single institution to obtain valuable clinical information. The NIH-sponsored multicentre OLT trial (200507) that is being performed in the USA will be very useful. A FIPSE-founded study (2006-08) is also being performed in Spain. For these reasons, it would be important to create an International Registry of cases, using standardized CRF in order to know the mid-term (5 year) and longterm (10 year) survival of OLT in HIV-infec­ted patients and to compare it with the non HIV-infected population. 3.  To improve the management of pharma­ cokinetic and pharmacodynamic in­te­ractions between immunosuppres­sive, antiretroviral and anti-HCV drugs. 4.  To know the most adequate immu­nosup­ pressive regimens for HIV-infected recipients. 5.  To know the natural history of OLT HCV reinfection and to improve the ma­nage­ment and the treatment of HCV recurrence. Prospective studies evaluating the effectiveness of pretransplant anti-HCV therapy in HIVinfected patients or the early (preemptive) postOLT anti-HCV therapy are warranted.

Acknowledgements This document is dedicated to all our pa­tients and has come about thanks to the collaboration of many people and institutions.

Financial support Partially supported by the “Fundación para la Investigación y Prevención del Sida en España” (FIPSE grants 36465/03 and TOH/VIH05); the “Agencia de Ensayos Clínicos del Grupo de Estudio de Sida (AEC-GESIDA) de la Sociedad Española de Enfermedades Infec­ciosas

y Microbiología Clínica (SEIMC)”; the “Ministerio de Sanidad y Consumo”, “Instituto de Salud Carlos III”, Spanish Network for the AIDS Research (RD06/006), Madrid (Spain)”; and, by the “Fundación Máxímo Soriano Jiménez” (Barcelona, Spain); and CIBEREHD is funded by the Instituto de Salud Carlos III, Spain.

Authors’ disclosures of potential conflicts of interest None of the authors have any potential conflicts of interest with this review.

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**This single-centre study focused the negative impact of recur­ rent hepatitis C on coinfected recipients. 14 out of 27 patients died and 5-year survival was lower in coinfected patients (33%) in comparison with monoinfected ones (72%). 18. Schreibman I, Gaynor J, Jayaweera D, et al. Outcomes after orthotopic liver transplantation in 15 HIV-infected patients. Transplantation. 2007;84:697-705. 19. Coffin CS, Berg CL, Dove LM. Survival and risk of HBV recurrence in HIV-HBV coinfected liver transplant recipients: preliminary findings from the HIV-TR study. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007 [abstract 28]. 20. Grossi P, Gabbrielli F, De Cillia C, et al. The Italian experience of liver transplantation in HIV-Infected Individuals. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008. 21. Neff GW, Sherman KE, Eghtesad B, Fung J. Review article: current status of liver transplantation in HIV-infected patients. Aliment Pharmacol Ther. 2004;20:993-1000. 22. Mindikoglu AL, Regev A, Magder LS. Impact of HIV on sur­vival after liver transplantation: analysis of United Network for Organ Sharing database. Transplantation. 2008;85:359-68. **This American study enrolled 138 HIV-infected patients who unde­ rwent liver transplant in the cART era (1996-2006) and compa­ red them with the general population. It ob­served that the rate of survival at 2 and 3 years was sig­nificantly lower in the HCV/ HIV-HBV/HIV coinfected group. 23. Duclos-Vallée JC, Féray C, Sebagh M, et al. Survival and re­ currence of hepatitis C after liver transplantation in patients coinfected with HIV and HCV. Hepatology. 2008;47:407-17. **This French study found that survival rates at 2 and 5 years were 81/91% and 51/73% in HIV/HCV-coinfected patients and HCVmonoinfected patients, respectively (p = 0,004). 24. Miró JM, Montejo M, Castells L, et al. 3-year survival of HCV/ HIV-coinfected liver transplant recipients (OLT) is similar to that of HCV-monoinfected recipients. 47th ICAAC. Chi­cago, 2007. V-1732. 25. Hamers FF, Downs AM. The changing face of the HIV epidemic in Western Europe: what are the implications for public health policies? Lancet. 2004;364:83-94. 26. Rockstroh J, Mocroft A, Soriano V, et al. Influence of hepatitis C coinfection on HIV disease progression within the EuroSIDA Cohort. 9th European AIDS Conference. October, 2003. Warsaw, Poland. [abstract F12/4]. 27. Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to HAART and in­ creased mortality in the EuroSIDA cohort. AIDS. 2005;19: 593-601. 28. González-García JJ, Mahillo B, Hernández S, et al. Prevalences of hepatitis virus coinfection and indications for chro­nic HCV treatment and liver transplantation in Spanish HIV-infected patients. The GESIDA 29/02 and FIPSE 12185/01 Multicenter Study. Enferm Infecc Microbiol Clin. 2005;23:340-8. 29. O’Grady J, Taylor C, Brook G. Guidelines for liver trans­plantation in patients with HIV infection (2005). HIV Med. 2005;6(Suppl 2):149-53. **This document is a short and concise report re­ lated to the U.K. OLT inclusion criteria in HIV-infected pa­ tients. 30. Miró JM, Torre-Cisneros J, Moreno A, et al. GESIDA/GESITRASEIMC, PNS and ONT consensus document on solid organ transplant (SOT) in HIV-infected patients in Spain. March, 2005. Enferm Infecc Microbiol Clin. 2005;23:353-62. **This Spanish consensus document addressed the most important issues concerning liver, kidney and cardiac transplantation in the HIVinfected population. 31. Roland ME, Stock PG. Review of solid-organ transplantation in HIV-infected patients. Transplantation. 2003;75:425-9. 32. Radecke K, Fruhauf NR, Miller M, et al. Outcome after orthotopic liver transplantation in five HIV-infected patients with virus hepatitis-induced cirrhosis. Liver Int. 2005;25:101-8. 33. Stock PG, Roland M. Evolving clinical strategies for transplantation in the HIV-positive recipient. Transplantation. 2007;84: 563-71. 34. Grossi PA, Tumietto F, Costigliola P, et al. Liver transplantation In HIV-infected individuals: Results of the Italian Natio­nal Program. Transplant Int. 2005:18(Suppl 1):11. 35. Anonymous. Solid organ transplantation in the HIV-infected patient. Am J Transplant. 2004;4(Suppl 10):83-8.

36. Hirsch MS, Brun-Vezinet F, Clotet B, et al. Antiretroviral drug resistance testing in adults infected with HIV-1: 2003 recommendations of an International AIDS Society-USA Panel. Clin Infect Dis. 2003;37:113-28. 37. Liu LU, Schiano TD, Lau N, et al. Survival and risk of reci­divism in methadone-dependent patients undergoing liver transplantation. Am J Transplant. 2003;3:1273-7. 38. Roland M, Stock PG. Liver transplantation in HIV-infected recipients. Semin Liver Dis. 2006;26:273-84. 39. Miro JM, Murillas J, Laguno M, et al. Natural history and prog­ nosis of ESLD in Spanish HIV-1 infected patients: A pros­ pective cohort study of 104 patients (1999-2004). 10th European AIDS Conference. Dublin, Ireland. November, 2005 [abstract PS7/1]. 40. Pineda JA, Romero-Gomez M, Diaz-Garcia F, et al. HIV co­ infection shortens the survival of patients with HCV-related decompensated cirrhosis. Hepatology. 2005;41:779-89. **This retrospective case-control study showed the poor prog­nosis and short survival of HIV/HCV-coinfected patients in compari­ son with HCV-monoinfected patients after the first cirrhosis decompensation episode. 41. Merchante N, Giron-Gonzalez JA, Gonzalez-Serrano M, et al. Survival and prognostic factors of HIV-infected patients with HCV-related end-stage liver disease. AIDS. 2006;20:49-57. **This Spanish study described the prognostic factors of sur­ vival in coinfected patients with ESLD. 42. Maida I, Nunez M, Gonzalez-Lahoz J, Soriano V. Liver transplantation in HIV/HCV-coinfected candidates: what is the most appropriate time for evaluation? AIDS Res Hum Retroviruses. 2005;21:599-601. 43. Ragni MV, Eghtesad B, Schlesinger KW, et al. Pretransplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease. Liver Transpl. 2005;11:1425-30. **This single centre study showed that during the pretransplant eval­ uation, HIV-infected patients had a shorter survival compared to non HIV-infected subjects. 44. Subramanian A, Sulkowski M, Barin B, et al. MELD is the best predictor of pretransplant mortality in HIV-infected liver transplant candidates. 15th CROI. Boston, MA. February, 2008 [abstract 64]. 45. Cardenas A, Gines P. Management of complications of cirrhosis in patients awaiting liver transplantation. J Hepatol. 2005;42(Suppl 1):S124-33. 46. Llovet JM, Fuster J, Bruix J; Barcelona-Clinic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treat­ ment of hepatocellular carcinoma. Liver Transpl. 2004;10(Suppl 1):S115-120. 47. Agüero F, Laguno M, Moreno A, et al. Management of endstage liver disease in HIV-infected patients. Curr Op HIV/AIDS. 2007;2:474-81. 48. Merchante N, Jiménez-Saenz M, Pineda JA. Management of HCV-related end-stage liver disease in HIV-coinfected pa­tients. AIDS Rev. 2007;9:131-9. 49. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection. 2006 Recommendations of the International AIDS Society-USA Panel. JAMA. 2006;296:827-43. 50. Expert Committee of GESIDA and the National AIDS Plan. Recommendations from the GESIDA/Spanish AIDS Plan regarding antiretroviral treatment in adults with HIV infection (Update January 2007). Enferm Infecc Microbiol Clin. 2007; 25:32-53. 51. Wyles DL, Gerber J. Antiretroviral drug pharmacokinetics in hepatitis with hepatic dysfunction. Clin Infect Dis. 2005; 40: 174-81. 52. Back D, Gibbons S. The University of Liverpool HIV drug interactions website: http://www.hiv-druginteractions.org/fra­mes. asp?pharmacology/pharma_main.asp [with access: 29/ 04/2008]. 53. Tuset M, Miró JM, Codina C, Ribas J, Ed. Guía de interaccio­ nes en HIV: http://www.interaccionesHIV.com [with access: 29/04/2008]. 54. Roland ME, Bernard L, Braff J, Stock PG. Key clinical, ethical, and policy issues in the evaluation of the safety and ef­ fectiveness of solid organ transplantation in HIV-infected patients. Arch Intern Med. 2003;163:1773-8. 55. Samuel D, Weber R, Stock P, et al. Are HIV-infected patients candidates for liver transplantation? J Hepatol. 2008;48:697707. **This manuscript is an excellent overview related to the hot topics in this specific setting.

Fernando Agüero, et al.: Adult Liver Transplantation in HIV-1 Infected Patients 56. Norris S, Houlihan D. Liver transplantation in HIV-positive pa­ tients. Expert Rev Gastroenterol Hepatol. 2008;2:39-46. 57. Margolis, D, Kewn S, Coull JJ, et al. The addition of mycophe­ no­late mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. J Acquir Immune Defic Syndr. 2002;31:45-9. 58. Stock PG, Roland ME, Carlson L, et al. Kidney and liver trans­ plantation in HIV-infected patients: a pilot safety and ef­ficacy study. Transplantation. 2003;76:370-5. 59. Roland ME. Solid-organ transplantation in HIV-infected patients in the potent antiretroviral therapy era. Top HIV Med. 2004;12:73-6. 60. Vogel M, Voigt E, Michaelis HC, et al. Management of drug-todrug interactions between cyclosporine A and the protea­seinhibitor lopinavir/ritonavir in liver-transplanted HIV-infec­ted patients. Liver Transpl. 2004;10:939. 61. Frassetto LA, Baloum M, Roland ME, Carlson L, Stock P, Be­net LZ. Two-year evaluation of the interactions between antiretroviral medication and cyclosporine in HIV– liver and kidney transplant recipients. 10th CROI. Boston, MA, 2003. 62. Frassetto, M. Browne, A. Cheng, et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant. 2007;7: 2816-20. 63. Tseng A, Nguyen ME, Cardella C, et al. Probable interaction between efavirenz and cyclosporine. AIDS. 2002;16:505-6. 64. Teicher E, Vittecoq D, Taburet AM, et al. Liver transplantation in HIV-coinfected patients treated by enfuvirtide. 13th CROI. Denver, CO, USA. February, 2006 [abstract 874]. 65. Moreno A, Bárcena A, Quereda C et al. Safe use of raltegra­vir and sirolimus in an HIV-infected patient with renal impairment after orthotopic liver transplantation. AIDS. 2008; 22:547-8. 66. Soriano V, Puoti M, Sulkowski M et al. Care of patients co­in­ fected with HIV and HCV: 2007 updated recommendations from the HCV-HIV International Panel. AIDS. 2007;21:1073-89. *This comprehensive review written by an international panel updates the recommendations for the essential areas of the HCV/HIVcoinfection setting. 67. Castells L, Esteban J, Bilbao I, et al. Early antiviral treatment of HCV recurrence after liver transplantation in HIV-infected pa­ tients. Antiviral Therapy. 2006;11:1061-70. 68. Vennarecci G, Mutimer D, Ettorre G, et al. Liver transplantation in HIV positive Patients. The 2006 Joint International Con­gress of ILTS, ELITA, LICAGE. Milan (Italy) May, 2006. Abstract num-













ber 457. Published at: Liver Transplantation. 2006;12(Suppl 1): C-115. 69. Castells L, Escartin A, Bilbao I, et al. Liver transplantation in HIV/HCV-coinfected patients: a case-control study. Transplantation. 2007;83:354-8. 70. Miro JM, Montejo M, Castells LL, et al. Treatment of Spanish HIV-infected patients with recurrent HCV after liver transplantation (OLT) with PEG-IFN plus ribavirin: Preliminary re­sults of the FIPSE OLT-HIV-05 - GESIDA 45-05 Cohort Study (200206). 14th CROI. Los Angeles, California. February, 2007 [abstract 890]. 71. Emmelkamp J, Guaraldi G, Cocchi S, et al. Antiviral therapy for HCV-recurrence after liver transplantation in HIV/HCV-in­fected individuals. 11th European AIDS Conference/EACS. Oc­tober 2007, Madrid. 72. Bhagat V, Foont J, Schiff E, et al. Spontaneous clearance of HCV after liver transplantation in two patients coinfected with HCV and HIV. Liver Transpl. 2008;14:92-5. 73. Soriano V, Puoti M, Bonacini M, et al. Care of patients with chronic hepatitis B and HIV coinfection: recommendations from an HIV-HBV International Panel. AIDS. 2005;19:221-40. *This document is a consensus which addresses the most re­levant and conflicting topics in the management of chronic hepatitis B in the setting of HIV infection. 74. Terrault NA, Carter JT, Carlson L, Roland ME, Stock PG. Out­ come of patients with HBV and HIV infections referred for liver transplantation. Liver Transpl. 2006;12:801-7. 75. Puoti M, Bruno R, Soriano V, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS. 2004;18:2285-93. *This Italian study compared the clinical and epidemiological aspects of HCC between 41 HIV-infected and 384 non HIV patients. 76. Bräu N, Fox RK, Xiao P, et al. Presentation and outcome of he­patocellular carcinoma in HIV-infected patients: a U.S.-Ca­na­ dian multicenter study. J Hepatol. 2007;47:447-50. 77. Chan A, Poo R, Ng K, et al. Changing paradigm in the ma­na­ gement of hepatocellular carcinoma improves the survival benefit of early detection by screening. Ann Surg. 2008;247: 666-73. 78. Di Benedetto F, de Ruvo N, Berretta M, et al. Don’t deny li­ver transplantation to HIV patients with hepatocellular carcinoma in the HAART era. J Clin Oncol. 2006;24:e26-7. 79. Di Benedetto F, De Ruvo N, Berretta N, et al. Hepatocellular carcinoma in HIV patients treated by liver transplantation. EJSO. 2008;34:422-7.

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Trends in Transplant. Transplantation 2008;2:92-100 2008;2

Optimal Length of Valganciclovir Prophylaxis after Solid Organ Transplantation Albert J. Eid1,4, Carlos V. Paya2 and Raymund R. Razonable1-3 1

Division of Infectious Diseases, 2Department of Medicine and 3William J. von Liebig Transplant Center, Mayo Clinic College of Medicine, Rochester, MN, USA; 4Division of Infectious Diseases, University of Kansas Medical Center, Kansas City, KS, USA

Abstract Purpose: Valganciclovir is the most commonly used drug for prophylaxis against cytomegalovirus after solid organ transplantation. In this article, we review the contemporary experience and clinical trial data that support the use of valganciclovir prophylaxis among solid organ transplantation populations. Methods: Review of clinical trials, observational studies, review articles, consensus statements, and guidelines on the use of valganciclovir prophylaxis after solid organ transplantation. Results: Three months of valganciclovir prophylaxis is recommended to all cytomegalovirus donor-positive/recipient-negative kidney, pancreas, heart, and liver transplant recipients. Based on an expert panel consensus, valganciclovir prophylaxis may be prolonged to ≥ 6 months in cytomegalovirus recipient-positive and cytomegalovirus donor-positive/recipient-negative lung transplant recipients. As an alternative to preemptive therapy, three months of valganciclovir prophylaxis is also recommended to cytomegalovirus recipient-positive kidney, pancreas, heart, and liver transplant recipients; this approach has resulted in an almost complete prevention of cytomegalovirus disease in cytomegalovirus recipient-positive solid organ transplant recipients. In contrast, cytomegalovirus donor-positive/recipient-negative solid organ transplant recipients remain at increased risk of primary cytomegalovirus disease, albeit at a delayed onset after transplantation. The emergence of delayed-onset cytomegalovirus disease in roughly 25% of cytomegalovirus donor-positive/recipient-negative solid organ transplant recipients raises the question on the optimal duration of prophylaxis in highrisk transplant populations. Preliminary data from single-center studies suggest that prolonging the duration to six months further reduces the incidence of cytomegalovirus disease in cytomegalovirus donor-positive/recipient-negative kidney recipients, although the safety of this approach in terms of drug toxicity and resistance is yet to be prospectively evaluated. In this regard, there is an ongoing clinical trial comparing 100 versus 200 days of

Correspondence to: Raymund R. Razonable Division of Infectious Diseases Mayo Clinic College of Medicine 200 First Street SW Rochester, MN, 55905 USA E-mail: [email protected]

92

Albert J. Eid, et al.: Duration of Valganciclovir Prophylaxis

valganciclovir prophylaxis in cytomegalovirus donor-positive/recipient-negative kidney transplant recipients and this is anticipated to provide guidance as to the optimal duration of valganciclovir prophylaxis in this high-risk population. Conclusions: The optimal duration of valganciclovir prophylaxis is variable, depending on the cytomegalovirus donor/recipient status, type of organ transplanted, risk of allograft rejection, and intensity of immunosuppression. Our continued effort to redefine the optimal duration of valganciclovir prophylaxis is anticipated to lead to better management and outcome of solid organ transplant recipients. (Trends in Transplant. 2008;2:92-100) Corresponding author: Raymund R. Razonable, [email protected]

Key words Valganciclovir. Antiviral prophylaxis. Solid organ transplantation. Outcome. Cytomegalovirus.

Introduction Since the advent of transplantation, cyto­ me­galovirus (CMV) has remained as the sin­gle most common pathogen that has influen­ced clinical outcome1. Cytomegalovirus causes direct clinical illness, manifested as fever, myelosuppression, and tissue-invasive disease. In the absence of antiviral prophylaxis, these direct CMV effects occur most com­monly during the first three months after solid organ transplantation. Through indirect and immunomodulatory mechanisms, CMV also increases the risk of allograft dysfunction and other opportunistic infections. The risk of developing the direct and indirect effects of CMV is highest among CMV-seronegative recipients of solid allografts from CMV-seropositive donors (CMV D+/R–) and among CMV-seropositive transplant recipients receiving lymphocyte-de­pleting drugs such as muromonab-CD31. The two major strategies for preventing CMV disease after solid organ transplantation are: (i) antiviral prophylaxis, which provides antiviral drugs to all patients at risk of CMV disease; and (ii) preemptive therapy, which entails the administration of antiviral drugs when CMV is detected on routine surveillance using polymerase chain reaction or phosphoprotein 65 antigenemia. Several meta-analyses have demonstrated that both strat-

egies are highly effective in preventing CMV disease2-4. However, antiviral prophylaxis is currently the preferred method of CMV prevention, particularly among CMV D+/R– solid or­gan transplant recipients who have the highest risk of developing CMV disease. Antiviral prophylaxis also provides the added benefits of lower mortality rates and lo­wer incidence of opportunistic infections3. In this review, we provide an overview of the contemporary practice of anti-CMV prophylaxis in solid organ transplantation, with particular emphasis on the most commonly used drug – valganciclovir. In the process, we highlight the evolving need to re-define the optimal duration of valganciclovir prophylaxis in solid organ transplant recipients.

The evolution of cytomegalovirus prophylaxis: searching for the optimal drug and duration The practice of antiviral prophylaxis after solid organ transplantation has evolved over the years. Acyclovir, a guanosine analog inhibitor of viral DNA polymerase, was the first antiviral drug used for anti-CMV prophylaxis after kidney5,6, pancreas5,6, heart7, and liver8 transplantation, with modest and inconsistent efficacy. While some studies showed that oral acyclovir was efficacious for CMV prevention after kidney transplantation5,6, 93

Trends in Transplantation 2008;2

other studies did not show any beneficial effect9. In general, oral acyclovir lacked efficacy for CMV prevention after liver transplantation8,10, especially in CMV D+/R– patients. The modest effi­ca­cy of acyclovir seemed related to systemic drug exposure11. Hence, its prodrug va­la­cy­clovir, which provides higher bioavailability, was demonstrated to be highly efficacious for preventing CMV disease after kidney transplantation12. Some studies even demonstrated com­parable efficacy between valacyclovir and ganciclovir after kidney (but not after liver, heart, and lung) transplantation13,14.

and di­sease (60 vs. 29%; p < 0.05) among CMV D+/R– kidney recipients23. Compared to placebo, oral ganciclovir given for 98 days redu­ced the sixmonth incidence of CMV infection (51.5 vs. 24.5%; p < 0.001) and CMV di­sease (19 vs. 5%; p < 0.001) in liver recipients21, in­clu­­ding CMV D+/R– patients (44 vs. 15%; p = 0.02) and patients who received an­tilymphocyte antibodies (33 vs. 5%; p = 0.002)21. Among the lower-risk CMV R+ liver recipients, oral ganciclovir for 12 weeks reduced the incidence of CMV disease to 1% (compared to 7% among patients who received acyclovir)25.

Ganciclovir, a guanosine analog inhibitor of viral DNA polymerase, is highly active against CMV in vitro15 and generally provides better efficacy when compared to acyclovir in the prevention of CMV disease after solid organ transplantation16,17. However, when given for only 14 days, intravenous (IV) ganciclovir was not effective in reducing the incidence of CMV disease in a cohort of CMV D+/R– kidney transplant recipients18,19. Prolonging the duration of IV ganciclovir prophylaxis to 28 days resulted in better efficacy among CMV R+ heart recipients, but not CMV D+/R– heart/lung recipients and CMV R+ lung recipients20. The results of these studies suggested that prophylaxis for longer than 28 days may be necessary for preventing CMV disease, at least among high-risk CMV D+/R– solid organ transplant populations. These clinical observations reflect the natural history of CMV disease, which traditionally occurs during the first three months after transplantation12.

The poor bioavailability of oral ganciclovir, however, results in low systemic levels that have been postulated to facilitate the emergence of drug-resistant CMV. Its L-valyl ester, valganciclovir, circumvents this by providing 60% bioavailability26. Pharmacokinetic studies indicate that standard valganciclovir dosing achieves a similar daily area under the concentration time curve (AUC24) as the standard dose of IV ganciclovir27. In a landmark randomized, prospective, multicenter study that compared valganciclovir (900 mg daily) and oral ganciclovir (1 gm three-times daily) prophylaxis for 100 days in a cohort of 364 solid organ transplant recipients (referred to as the PV16000 trial), the incidences of CMV disease at six months (12.1 vs. 15.2%) and 12 months (17.2 vs. 18.2%) were comparable between valganciclovir or oral ganciclovir, respectively22. Moreover, there was a lower incidence of viremia during prophylaxis, longer time-to-viremia, and lower peak viral load in the valganciclovir group22. Supported by this clinical data and its pharmacokinetic profile, valganciclovir has emerged as the most commonly used drug for antiviral prophylaxis after solid organ transplantation28.

Subsequent clinical trials have therefore extended the duration of prophylaxis to three months after solid organ transplantation21-23. The administration of IV ganciclovir for 90-100 days reduced the incidence of CMV disease in CMV D+/R– liver transplant recipients to 5.4% (compared to 40% in patients who received < 7 weeks of prophylaxis)24. The major drawback to IV ganciclovir, however, was the need for long-term vascular access and the associated risks of thrombosis, phlebitis, and lineassociated infections. When the oral formulation of ganciclovir became available, it was demonstrated that when given for three months, it reduced the incidence of CMV infection (75 vs. 45%; p < 0.05) 94

The evolution of antiviral prophylaxis after solid organ transplantation has also seen the use of CMV hyperimmune globulin, alone or in combination with antiviral drugs. A recent meta-analysis, however, failed to show significant benefit in terms of CMV disease prevention, although it was associated with redu­ced mortality29. Foscarnet and cidofovir, both acting as inhibitors of viral DNA polymerase, are highly active in vitro against

Albert J. Eid, et al.: Duration of Valganciclovir Prophylaxis

Table 1. Estimated incidence of CMV disease in various solid organ transplant recipients CMV D+/R– Type of transplant

CMV R+

No prophylaxis

With prophylaxis*

No prophylaxis

With prophylaxis*

Kidney and/or pancreas

45-65%

6-29%

8-10%

1-2%

Liver

45-65%

6-29%

8-19%

4-13%

Heart

29-74%

19-30%

20-40%

2%

Lung and lung/heart

50-91%

36-40%* 10%†

35-59%

10%* < 5%†

CMV: cytomegalovirus; D+/R–: donor positive, recipient negative; R+, recipient positive. Data were estimated based on clinical trials and retrospective and observational studies, as discussed in the text22,32,35,38,42,53,55. *Prophylaxis given for a duration of 3 months unless otherwise indicated (†indicates 6 months of prophylaxis after lung transplantation). CMV disease in patients who received prophylaxis generally occurs after the completion of antiviral prophylaxis (delayed-onset CMV disease).

CMV, but the risk of associated nephrotoxicity has limited their use in solid organ transplantation. Antiviral prophylaxis continues to evolve, as illustrated by the ongoing clinical trial of maribavir, a novel anti-CMV drug that acts as a UL97 kinase inhibitor, for the prevention of primary CMV disease after liver transplantation.

Valganciclovir prophylaxis after kidney and pancreas transplantation In the absence of antiviral prophylaxis, it is estimated that 8-32% of all kidney recipients and up to 50% of all pancreas recipients will develop CMV infection and disease after transplantation30. With three months of valganciclovir prophylaxis, the estimated incidence has been reduced to 2.9-17% (Table 1)31,32. The risk of CMV disease is primarily dependent on the CMV donor and recipient serologic status. In the absence of antiviral prophylaxis, the incidence of CMV disease among CMV R+ kidney/pancreas recipients is estimated at 10%. This incidence has been reduced to 1% among CMV R+ kidney recipients who received three months of antiviral (va­lacyclovir) prophylaxis12. Valganciclovir has not been rigorously studied in CMV R+ kidney/pancreas recipients; however, it is believed to be highly effective in preventing CMV disease in this population. Currently, as an alternative to preemptive therapy, valganciclovir prophylaxis for three months is

recommended for the prevention of CMV disease in CMV R+ kidney/pancreas recipients. In the absence of anti-CMV prophylaxis, CMV D+/R– kidney/pancreas recipients have a higher estimated incidence of CMV disease (4565%)5,12. Because of this high risk of CMV disease, it is recommended that CMV D+/R– kidney/ pancreas recipients receive valganciclovir prophylaxis for three months after transplantation33. This recommendation is supported by findings of the PV16000 trial, which included 132 kidney and/or pancreas recipients22. In sub­group ana­ lysis, kidney and pancreas recipients who received valganciclovir for three months had a lower sixmonth incidence of CMV disease compared to those who received oral ganciclovir prophylaxis (6 vs. 23% for kid­ney recipients, and 0 vs. 17% for kidney/pancreas recipients, respectively)22. Several retrospective studies have confirmed that valganciclovir prophylaxis for three months reduced the incidence of CMV disea­se in CMV D+/R– kidney/pancreas recipients, although not to the same extent as demonstrated in the PV16000 trial34. Most re­tros­pec­tive studies have reported that 25-30% of CMV D+/R– kidney/pancreas recipients who received three months of valganciclovir prophylaxis develop delayed-onset primary CMV disease35,36. Allograft rejection, presence of medical comorbidities, and the occurrence of bacterial and fungal infections predispose to the development of delayed-onset 95

Trends in Transplantation 2008;2

primary CMV disease35. Moreover, delayed-onset CMV disease has been associated with allograft loss and mortality after kidney transplantation35. To this end, an important question is raised: What is the optimal length of valganciclovir prophylaxis to prevent CMV disease? Will prolongation of valganciclovir prophylaxis beyond the standard three months duration result in further reduction in CMV disease incidence without a corresponding in­crease in associated risk? To address this issue, a randomized clinical trial is being conducted to evaluate the efficacy and safety of 100 vs. 200 days of valganciclovir prophylaxis in CMV D+/R– kidney recipients. While the results of this clinical trial are eagerly awaited, the findings of recent single-center trials may foreshadow the anticipated outcome. In one of these studies, the incidence of CMV disease was significantly further reduced among CMV D+/R– kidney recipients who received 24 weeks com­­ pared to 12 weeks of oral ganciclovir prophylaxis (6.5 vs. 31%, respectively)37. In another stu­dy, prolonging valganciclovir prophylaxis from three to six months led to a further decline in incidence of CMV disease from 25 to 5% among thymoglobulin-treated kidney recipients38. However, as some transplant cen­ters are now adapting a more prolonged prophylactic approach in high-risk CMV D+/R– kidney and pancreas recipients37-38, one should be cautious as to its potential risks such as the adverse effects of bone marrow suppression and the possible emergence of difficult-to-manage and sometimes fatal drug-resistant CMV39,40.

Valganciclovir prophylaxis after liver transplantation In the absence of anti-CMV prophylaxis, the overall estimated incidence of CMV disease after liver transplantation is 22-29%21,30. However, the incidence can be as high as 45-65% among CMV D+/R– liver recipients, or as low as 8-19% among CMV R+ liver recipients who are not receiving antiviral prophylaxis21. Valganciclovir and oral ganciclovir prophylaxis have significantly reduced the incidence of CMV disease in all CMV 96

D+/R– and CMV D/R+ serogroups. However, based on the results of the PV16000 trial22, the efficacy of valganciclovir prophylaxis in liver recipients appears to be significantly less compared to kidney, pancreas, and heart recipients22. Additionally, there is an ongoing debate as to which of the drugs (valganciclovir or oral ganciclovir) is more effective for CMV disease prevention among CMV D+/R– liver recipients. Among 177 CMV D+/R– liver recipients who participated in the PV16000 trial, the six-month incidence of CMV disease was 19% in the valganciclovir group compared to 12% in the oral ganciclovir group22. As a result, the U.S. Food and Drug Administration (FDA) did not approve of the use of valganciclovir prophylaxis in CMV D+/R– liver recipients. Nonetheless, a survey of transplant centers across the USA and Canada showed that valganciclovir is the most common drug used for CMV prophylaxis after liver transplantation28. Several single-center studies have estimated that CMV disease occurs in up to 30% of CMV D+/R– liver recipients after they complete three months of valganciclovir prophylaxis (i.e. delayed-onset CMV disease) (Table 1)41,42. In one retrospective study, CMV disease was observed in 14 of 54 (26%) CMV D+/R– liver recipients who received at least three months of valganciclovir prophylaxis43. Our clinical experience also suggests that, while no breakthrough CMV disease occurred during valganciclovir prophylaxis, about 29% of CMV D+/R– liver recipients will eventually develop CMV disease at a delayed onset (between 3-6 months) after liver transplantation42. Studies have reported that age, female gender, renal dysfunction, and allograft rejection predisposes to the development of delayed-onset primary CMV disease (Table 2)41,42,44,45. Delayed-onset CMV disease has also been significantly associated with mortality after liver transplantation46. Hence, a better strategy for CMV prevention is warranted. Among CMV R+ liver recipients, oral gan­ ciclovir prophylaxis has reduced the incidence of CMV disease from 8-19% to less than 4%21, suggesting that a three-month duration of oral

Albert J. Eid, et al.: Duration of Valganciclovir Prophylaxis

ganciclovir prophylaxis is likely sufficient in CMV R+ liver recipients. However, clinical data suggest that the efficacy of valganciclovir in preventing CMV disease in CMV R+ liver recipients is also possibly less when compared to oral ganciclovir. While valganciclovir has not been subjected to rigorous controlled clinical trials in CMV R+ liver recipients, one observational study demonstrated that 13% of CMV R+ liver recipients, especially the CMV D+/R+ group, developed CMV infection and disease, despite three months of valganciclovir prophylaxis43.

Valganciclovir prophylaxis after heart and lung transplantation The risk of CMV infection and disease after thoracic organ transplantation varies, depending on the organ transplanted and the CMV D/R serostatus. In the absence of antiviral prophylaxis, it is estimated that up to 75% of lung recipients47 and 21-50% of heart recipients develop CMV disease30. As in other solid organ transplant groups, the risk of CMV disease is highest among CMV D+/R– patients (Table 1), and the use of valganciclovir or oral and IV ganciclovir has significantly reduced the incidence of CMV disease among thoracic organ transplant recipients. The current guidelines recommend three months of valganciclovir to all CMV D+/R– patients and, as an alternative to preemptive therapy, to CMV R+ heart recipients. In a subgroup analysis of the 56 CMV D+/R– heart recipients that participated in the PV16000 trial, the sixmonth incidence of CMV disease was 6% in the valganciclovir group and 10% in the ganciclovir group22. However, as with other CMV D+/R– solid organ transplant groups, the incidence of delayed-onset primary CMV disease that is seen in clinical practice (i.e. outside of the controlled clinical trial setting) is estimated at 30% of all CMV D+/R– heart recipients, with almost all cases occurring after the completion of three months of valganciclovir prophylaxis (i.e. delayed-onset CMV disease)48. Acute rejection enhances the risk of developing CMV disease, despite valganciclovir prophylaxis (Table 2)48.

Table 2. Risk factors for delayed onset cytomegalovirus disease in solid organ transplant recipients 1. CMV D+/R– serostatus 2. Acute allograft rejection 3. Over-immunosuppression 4. Female gender 5. Comorbidity 6. Renal insufficiency 7. Bacterial infection 8. Fungal infection CMV: cytomegalovirus; D+/R–: donor positive and recipient negative serostatus.

In contrast to the other solid organ transplant populations, clinical studies suggest that a longer period of valganciclovir prophylaxis is necessary for the prevention of CMV disease in CMV D+/R– and CMV R+ lung and heart/lung transplant recipients47,49-52. Indeed, despite 12 weeks of valganciclovir or oral and IV ganciclovir prophylaxis, the incidence of CMV infection and disease remains high among lung recipients. In one study of CMV D+/R– and R+ lung recipients that compared valganciclovir vs. IV ganciclovir (CMV D+/R–) or oral ganciclovir (CMV R+) prophylaxis for 12 weeks, there was a comparable incidence of CMV infection (40% with valganciclovir vs. 45% with IV or oral ganciclovir) and disease (20% with valganciclovir vs. 17.5% with IV or oral ganciclovir)53. The high rates of CMV disease despite three months of valganciclovir prophylaxis has led other transplant centers, including ours, to prolong valganciclovir prophylaxis, especially among CMV D+/R– lung recipients54. In one single-center study that assessed the optimal duration of valganciclovir prophylaxis in CMV D+/R– and R+ lung recipients, it was demonstrated that at least 180 days of valganciclovir prophylaxis was necessary to remarkably reduce the incidence of CMV infection and disease after lung transplantation55. Following an initial prophylaxis using a combination of CMV immunoglobulin and IV ganciclovir (for 90 days in CMV D+/R– or 30 days in R+ lung recipients), valganciclovir prophylaxis was administered for 180, 270, and 365 days. 97

Trends in Transplantation 2008;2

Freedom from CMV infection and disease was significantly higher among patients who received 180 (90%), 270 (95%), or 365 (90%) days of valganciclovir prophylaxis, compared to those who received only 100-179 days (64%) or < 100 days (59%) of valganciclovir prophylaxis55. However, our anecdotal experience suggests that, regardless of the duration of antiviral prophylaxis, lung recipients will remain at high risk of CMV disease so long as they remain CMV-seronegative, as illustrated by a patient who developed primary CMV disease despite five years of antiviral prophylaxis56.

Optimal length of valganciclovir prophylaxis: balancing benefits and risks As illustrated above, a multitude of clinical factors influence the length of valganciclovir prophylaxis after solid organ transplantation, and hence the dictum of “one size fits all” does not necessarily apply. Indeed, an individualized approach is needed to define the optimal length for each transplant recipient. The clinical factors that could influence the optimal duration of valganciclovir prophylaxis are CMV D/R serostatus, allograft rejection, use of antilymphocyte antibodies, and the net state of immunosuppression. Based on available clinical data, CMV R+ kidney, pancreas, liver, and heart recipients may be managed either with preemptive valganciclovir therapy (if the tools necessary for optimal CMV surveillance are available) or three months of valganciclovir prophylaxis. In some patients, such as those with acute rejection and those receiving lymphocyte-depleting immunosuppressive drugs, one may prolong the duration of prophylaxis on a ca­se-by-case basis, at least until the intensity of pharmacologic immunodeficiency has been remarkably reduced. In the vast majority of CMV R+ kidney, pancreas, liver, and heart recipients, three months of valganciclovir is likely sufficient to prevent CMV disease. In contrast, the emergence of delayed-onset primary CMV disease has challenged the optimal duration of valganciclovir prophylaxis among CMV D+/R– solid organ transplant recipients. Cur98

rently, CMV D+/R– kidney, pancreas, liver, and heart recipients are recommended to receive at least three months of valganciclovir prophylaxis, while CMV R+ and CMV D+/R– lung recipients should receive at least six months of valganciclovir. Despite this approach, however, CMV D+/R– solid organ transplant recipients remain at high risk of de­layed-onset primary CMV disease after completion of valganciclovir prophylaxis, particularly when they remain CMV-seronegative or they are severely immunosuppressed as a result of therapy for allograft rejection. Clinical states associated with “cytokine storm”, such as allograft rejection and bacterial and fungal infections, have also been associated with delayed-onset CMV disease. Because delayed-onset CMV disease is associated with poor allograft and patient survival, one may argue to re-define the strategy for CMV prevention in this high-risk cohort. Whether this is best approached by prolonging valganciclovir prophylaxis to all at-risk patients or by a targeted approach (given only to those with defined clinical risks such as allograft rejection) remains to be evaluated. A list of known clinical factors associated with increased risk of delayed-onset CMV disease is listed in table 2. To illustrate the potential benefit of this approach, we have shown that since we have re-initiated 1-3 additional months of valganciclovir prophylaxis to CMV D+/R– liver, kidney, and heart recipients who developed acute allograft rejection, the incidence of CMV disease has been reduced in this group. Using this example, one may find it reasonable to extend the duration of valganciclovir prophylaxis to a period of less intense immunosuppression. Currently, the randomized clinical trial comparing standard (100 days) vs. prolonged (200 days) duration of valganciclovir prophylaxis in CMV D+/R– kidney recipients is about to be completed. It is anticipated that this trial will advance clinical practice by defining better strategies for CMV prevention. We anticipate that this prolonged prophylaxis approach will lead to further reduction of CMV disease. However, this will not likely lead to com­ plete protection against CMV disease since CMV D+/R– solid organ transplant recipients and those

Albert J. Eid, et al.: Duration of Valganciclovir Prophylaxis

who have absent or deficient CMV-specific T-cell immunity57 will remain at risk of CMV disease during the posttransplant period as long as they remain CMV-seronegative or severely immunosuppressed. Importantly, it will be important to assess the additional risks associated with prolonging valganciclovir prophylaxis, in terms of drug resistance40 and adverse effects such as leucopenia and neutropenia39.

Conclusion Valganciclovir prophylaxis is the most common method for the prevention of CMV disease after solid organ transplantation. Clinical evidence suggests that three months of valganciclovir prophylaxis is highly efficacious in CMV disease prevention, especially among CMV R+ kidney, pancreas, liver, and heart recipients. However, CMV D+/R– solid organ transplant recipients remain at high risk of delayed-onset primary CMV disease despite three months of valganciclovir prophylaxis. This emergence of delayed-onset CMV disease challenges the current clinical practice and raises the important question: What is the optimal length of valganciclovir prophylaxis? Prolonging the duration of valganciclovir prophylaxis to a period of less intense (i.e. minimal) immunosuppression could theoretically protect patients from delayed-onset CMV disease. In this regard, one should consider the CMV D/R status, the type of organ transplanted, the ongoing risk of rejection, and the intensity of immunosuppression in defining the optimal duration of valganciclovir prophylaxis. It is anticipated that our ongoing search for the optimal length of valganciclovir prophylaxis will lead to better management and outcome of our most vulnerable solid organ transplant recipients.

Acknowledgements Research support to Raymund R Razonable from Department of Medicine, and the William J von Liebig Transplant Center.

References

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trolled trials. Lancet. 2005;365:2105-15. *This meta-analysis of randomized clinical trials demonstrated the benefits of antiviral drugs for prophylaxis against CMV disease in solid organ trans­ plant recipients. A reduction in all-cause mortality was also demonstrated in patients receiving antiviral prophylaxis. 3. Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG. Meta-analysis: the efficacy of strategies to prevent organ disease by CMV in solid organ transplant recipients. Ann Intern Med. 2005;143:87080. *This meta-analysis of randomized clinical trials demonstrat­ ed the benefits of antiviral drugs for prophylaxis against CMV disease in solid organ transplant recipients. 4. Small LN, Lau J, Snydman DR. Preventing post-organ transplantation CMV disease with ganciclovir: a meta-analysis comparing prophylactic and preemptive therapies. Clin Infect Dis. 2006;43:869-80. *This meta-analysis of randomized clinical tri­ als demonstrated the benefits of antiviral drugs for prophylaxis against CMV disease in solid organ transplant recipients. 5. Vila A, Guirado LL, Balius A, et al. Acyclovir prophylaxis of CMV disease in kidney transplant recipients. Transplant Proc. 1999; 31:2335-6. 6. Balfour HH, Chace BA, Stapleton JT, Simmons RL, Fryd DS. A randomized, placebo-controlled trial of oral acyclovir for the prevention of CMV disease in recipients of renal allografts. N Engl J Med. 1989;320:1381-7. 7. Egan JJ, Carroll KB, Yonan N, Woodcock A, Crisp A. Valacyclovir prevention of CMV reactivation after heart transplantation: a randomized trial. J Heart Lung Transplant. 2002;21:460-6. 8. Martin M, Manez R, Linden P, et al. A prospective randomized trial comparing sequential ganciclovir-high dose acyclovir to high dose acyclovir for prevention of CMV disease in adult liver transplant recipients. Transplantation. 1994;58:779-85. 9. Wong T, Lavaud S, Toupance O, et al. Failure of acyclovir to prevent CMV infection in renal allograft recipients. Transpl Int. 1993;6:285-9. 10. Badley AD, Seaberg EC, Porayko MK, et al. Prophylaxis of CMV infection in liver transplantation: a randomized trial comparing a combination of ganciclovir and acyclovir to acyclovir. NIDDK Liver Transplantation Database. Transplantation. 1997;64:66-73. 11. Fiddian P, Sabin CA, Griffiths PD. Valacyclovir provides optimum acyclovir exposure for prevention of CMV and related outcomes after organ transplantation. J Infect Dis. 2002;186(Suppl 1):S110-5. 12. Lowance D, Neumayer HH, Legendre CM, et al. Valacyclovir for the prevention of CMV disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N Engl J Med. 1999;340:1462-70. 13. Reischig T, Opatrny K, Bouda M, Treska V, Jindra P, Svecova M. A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of CMV disease after renal transplantation. Transpl Int. 2002;15:615-22. 14. Yango A, Morrissey P, Zanabli A, et al. Comparative study of prophylactic oral ganciclovir and valacyclovir in high-risk kidney transplant recipients. Nephrol Dial Transplant. 2003; 18:809-13. 15. Keating MR. Antiviral agents. Mayo Clin Proc. 1992;67:160-78. 16. Somerville T, Hurst G, Alloway R, Gaber A, Shokouh-Amiri MH, Stratta R. Superior efficacy of oral ganciclovir over oral acyclovir for CMV prophylaxis in kidney-pancreas and pancreas alone recipients. Transplant Proc. 1998;30:1546-8. 17. Flechner SM, Avery RK, Fisher R, et al. A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for CMV prophylaxis in high-risk kidney transplant recipients. Transplantation. 1998;66:1682-8. 18. Rondeau E, Bourgeon B, Peraldi MN, et al. Effect of prophylactic ganciclovir on CMV infection in renal transplant recipients. Nephrol Dial Transplant. 1993;8:858-62. 19. Dunn DL, Gillingham KJ, Kramer MA, et al. A prospective randomized study of acyclovir versus ganciclovir plus human immune globulin prophylaxis of CMV infection after solid organ transplantation. Transplantation. 1994;57:876-84. 20. Merigan TC, Renlund DG, Keay S, et al. A controlled trial of ganciclovir to prevent CMV disease after heart transplantation. N Engl J Med. 1992;326:1182-6. 21. Gane E, Saliba F, Valdecasas GJ, et al. Randomized trial of efficacy and safety of oral ganciclovir in the prevention of CMV disease in liver transplant recipients. The Oral Ganciclovir International Transplantation Study Group [corrected]. Lancet. 1997;350:1729-33.

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39. Eid AJ, Razonable RR. Cytomegalovirus disease after solid organ transplantation: Advances lead to challenges and opportunities. Curr Opin Organ Transplant. 2008;12:610-17. 40. Eid AJ, Arthurs SK, Deziel P, Wilhelm MP, Razonable RR. Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis. Clin Transplant. 2008 [in press]. 41. Razonable RR, Rivero A, Rodriguez A, et al. Allograft rejection predicts the occurrence of late-onset CMV disease among CMV-mismatched solid organ transplant patients receiving prophylaxis with oral ganciclovir. J Infect Dis. 2001;184:1461-4. 42. Arthurs SK, Eid AJ, Pedersen RA, et al. Delayed-onset primary CMV disease after liver transplantation. Liver Transpl. 2007;13:1703-9. 43. Jain A, Orloff M, Kashyap R, et al. Does valganciclovir hydrochloride (valcyte) provide effective prophylaxis against CMV infection in liver transplant recipients? Transplant Proc. 2005; 37:3182-6. 44. Freeman RB, Paya C, Pescovitz MD, et al. Risk factors for CMV viremia and disease developing after prophylaxis in high-risk solid-organ transplant recipients. Transplantation. 2004;78: 1765-73. 45. Limaye AP, Bakthavatsalam R, Kim HW, et al. Late-onset CMV disease in liver transplant recipients despite antiviral prophylaxis. Transplantation. 2004;78:1390-6. 46. Limaye AP, Bakthavatsalam R, Kim HW, et al. Impact of CMV in organ transplant recipients in the era of antiviral prophylaxis. Transplantation. 2006;81:1645-52. 47. Speich R, Thurnheer R, Gaspert A, Weder W, Boehler A. Efficacy and cost effectiveness of oral ganciclovir in the prevention of CMV disease after lung transplantation. Transplantation. 1999;67:315-20. 48. Kijpittayarit-Arthurs S, Eid AJ, Kremers WK, et al. Clinical features and outcomes of delayed-onset primary CMV disease in cardiac transplant recipients. J Heart Lung Transplant. 2007; 26:1019-24. 49. Perreas KG, McNeil K, Charman S, Sharples LD, Wreghitt T, Wallwork J. Extended ganciclovir prophylaxis in lung transplantation. J Heart Lung Transplant. 2005;24:583-7. 50. Gutierrez CA, Chaparro C, Krajden M, Winton T, Kesten S. Cytomegalovirus viremia in lung transplant recipients receiving ganciclovir and immune globulin. Chest. 1998;113:924-32. 51. Valantine HA, Luikart H, Doyle R, et al. Impact of CMV hyperimmune globulin on outcome after cardiothoracic transplantation: a comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir versus ganciclovir alone. Transplantation. 2001;72:1647-52. 52. Weill D, Lock BJ, Wewers DL, et al. Combination prophylaxis with ganciclovir and CMV immune globulin after lung transplantation: effective CMV prevention following daclizumab induction. Am J Transplant. 2003;3:492-6. 53. Humar A, Kumar D, Preiksaitis J, et al. A trial of valganciclovir prophylaxis for CMV prevention in lung transplant recipients. Am J Transplant. 2005;5:1462-8. *This multicenter study from Canada demonstrated that valganciclovir is as effective as IV or oral ganciclovir for the prevention of CMV disease in lung transplant recipients. 54. Zamora MR, Davis RD, Leonard C. Management of CMV infection in lung transplant recipients: evidence-based recommendations. Transplantation. 2005;80:157-63. *This is the consensus statement from a panel of experts. The experts recommended, based on evaluation of clinical trials and data, that valganciclo­ vir for 6 months is needed for the prevention of CMV disease in at-risk lung transplant recipients. 55. Zamora MR, Nicolls MR, Hodges TN, et al. Following universal prophylaxis with intravenous ganciclovir and CMV immune globulin, valganciclovir is safe and effective for prevention of CMV infection following lung transplantation. Am J Transplant. 2004;4:1635-42. *This single-center study from Colorado dem­ onstrated that valganciclovir prophylaxis is effective for the prevention of CMV disease in lung transplant recipients so long as it is administered for at least 180 days (6 months). 56. Kijpittayarit S, Deziel P, Eid AJ, Razonable RR. Primary CMV disease after five years of antiviral prophylaxis. Transplantation. 2006;81:137-8. 57. Sester M, Sester U, Gartner B, et al. Levels of virus-specific CD4 T cells correlate with CMV control and predict virus-induced disease after renal transplantation. Transplantation. 2001;71:1287-94.

1. NOMBRE DEL MEDICAMENTO. CellCept500 mg, comprimidos; CellCept250 mg, cápsulas; CellCept, 500 mg, polvo para concentrado para solución para perfusión.2. COMPOSICIÓN CUALITATIVA Y CUANTITATIVA. Cada comprimido contiene 500 mg de micofenolato mofetilo. Cada cápsula contiene 250 mg de micofenolato mofetilo.Cada vial contiene el equivalente a 500 mg de micofenolato mofetilo (clorhidrato). Excipientes: Para la lista completa, ver sección 6.1. 3. FORMA FARMACÉUTICA. Comprimidos recubiertos con película. Comprimidos CellCept: oblongos, de color azul espliego, con el grabado “CellCept 500” en una cara y el “logotipo de la Empresa” en la otra. Cápsulas duras. Cápsulas CellCept: oblongas, de color azul/marrón, con la inscripción “CellCept 250” en la mitad superior y el “logotipo de la Compañía” en la mitad inferior. Polvo para concentrado para solución para perfusión. CellCept 500 mg polvo para concentrado para solución para perfusión debe ser reconstituido y posteriormente diluido con una solución para perfusión intravenosa de glucosa al 5 %, antes de la administración al paciente (ver sección 6.6). 4. DATOS CLÍNICOS. 4.1 Indicaciones terapéuticas. CellCept, en combinación con ciclosporina y corticosteroides, está indicado para la profilaxis del rechazo agudo de trasplante en pacientes sometidos a trasplante alogénico renal, cardíaco o hepático. 4.2 Posología y forma de administración. El tratamiento con CellCept debe ser iniciado y mantenido por especialistas debidamente cualificados en trasplantes. ADVERTENCIA: LA SOLUCIÓN INTRAVENOSA DE CELLCEPT NUNCA DEBE SER ADMINISTRADA MEDIANTE INYECCIÓN INTRAVENOSA RÁPIDA O EN BOLUS. CellCept 500 mg polvo para concentrado para solución para perfusión es una forma farmacéutica alternativa a las formas orales de CellCept (cápsulas, comprimidos y polvo para suspensión oral) que puede ser administrada durante 14 días. La dosis inicial de CellCept 500 mg polvo para concentrado para solución para perfusión debe administrarse, dentro de las 24 horas siguientes al trasplante.Tras la reconstitución hasta una concentración de 6 mg/mL, CellCept 500 mg polvo para concentrado para solución para perfusión se debe administrar mediante perfusión intravenosa lenta en un período superior a 2 horas, bien en vena periférica o en vena central (ver sección 6.6). Uso en trasplante renal: Adultos: el inicio de la administración de CellCept por vía oral debe realizarse en las 72 horas siguientes al trasplante. La dosis recomendada en trasplantados renales es de 1 g administrado dos veces al día (dosis diaria total = 2 g). Niños y adolescentes (entre 2 y 18 años): la dosis recomendada de micofenolato mofetilo es de 600 mg/m2, administrada dos veces al día por vía oral (hasta un máximo de 2 g diarios). Los comprimidos de CellCept deben prescribirse únicamente a pacientes con una superficie corporal mayor de 1,5 m2, deben recibir una dosis de 1 g dos veces al día (dosis diaria total = 2 g). Debido a que algunas reacciones adversas ocurren con una mayor frecuencia en este grupo de edad (ver sección 4.8), en comparación con los adultos, es posible que sea necesario efectuar reducciones de dosis temporales o interrupción del tratamiento; esto deberá tener en cuenta factores clínicos relevantes incluyendo la gravedad del evento. Niños (< 2 años): existen datos limitados de seguridad y eficacia en niños con una edad inferior a los 2 años. Estos son insuficientes para realizar recomendaciones posológicas y por consiguiente, no se recomienda su uso en este grupo de edad. Uso en trasplante cardíaco: Adultos: el inicio de la administración de CellCept por vía oral debe realizarse en los 5 días siguientes al trasplante. La dosis recomendada en los pacientes sometidos a trasplante cardíaco es de 1,5 g administrada dos veces al día (dosis diaria total = 3 g). Niños: No hay datos disponibles en pacientes pediátricos con trasplante cardíaco. Uso en trasplante hepático: Adultos: se debe administrar CellCept IV durante los 4 días siguientes al trasplante hepático, posteriormente se comenzará la administración de CellCept oral, tan pronto como ésta sea tolerada. La dosis oral recomendada en los pacientes sometidos a trasplante hepático es de 1,5 g administrados dos veces al día (dosis total diaria = 3 g). Niños: No hay datos disponibles en pacientes pediátricos con trasplante hepático. Uso en ancianos (* 65 años): la dosis recomendada en ancianos es de 1 g administrado dos veces al día en el trasplante renal y 1,5 g dos veces al día en los trasplantes cardíaco y hepático. Uso en pacientes con insuficiencia renal: en pacientes sometidos a trasplante renal con insuficiencia renal crónica grave (filtración glomerular < 25 mL·min-1·1,73 m-2), deben evitarse dosis superiores a 1 g dos veces al día fuera del período inmediatamente posterior al trasplante. Se debe observar cuidadosamente a estos pacientes. No son necesarios ajustes posológicos en pacientes con retraso funcional del riñón trasplantado en el postoperatorio (ver sección 5.2).No existen datos sobre los pacientes sometidos a trasplante cardíaco o hepático con insuficiencia renal crónica grave. Uso en pacientes con insuficiencia hepática grave: los pacientes sometidos a trasplante renal con enfermedad grave del parénquima hepático, no precisan ajuste de dosis. No existen datos sobre los pacientes sometidos a trasplante cardíaco con enfermedad grave del parénquima hepático. Tratamiento durante episodios de rechazo: el ácido micofenólico (MPA) es el metabolito activo del micofenolato mofetilo. El rechazo del riñón trasplantado no provoca cambios en la farmacocinética del MPA; no es necesario reducir la dosis o interrumpir el tratamiento con CellCept. No hay fundamentos para ajustar la dosis de CellCept tras el rechazo del corazón transplantado. No se dispone de datos farmacocinéticos durante el rechazo del hígado trasplantado.4.3 Contraindicaciones. Se han descrito reacciones de hipersensibilidad a CellCept (ver sección 4.8). Por consiguiente, este medicamento está contraindicado en pacientes con hipersensibilidad al micofenolato mofetilo o al ácido micofenólico. CellCept está contraindicado en mujeres en periodo de lactancia (ver el sección 4.6). Para información sobre su uso durante el embarazo así como las medidas contraceptivas a adoptar ver sección 4.6. 4.4 Advertencias y precauciones especiales de empleo. Los pacientes que reciben CellCept como parte de un tratamiento inmunosupresor en combinación con otros medicamentos, presentan un mayor riesgo de desarrollar linfomas y otros tumores malignos, en especial de la piel (ver sección 4.8). El riesgo parece estar relacionado con la intensidad y la duración de la inmunosupresión más que con el uso de un fármaco determinado. Como norma general para minimizar el riesgo de cáncer de piel, se debe limitar la exposición a la luz solar y a la luz UV mediante el uso de ropa protectora y el empleo de pantalla solar con factor de protección alto. Se debe indicar a los pacientes que reciben tratamiento con CellCept que comuniquen inmediatamente cualquier evidencia de infección, contusiones no esperadas, hemorragias o cualquier otra manifestación de depresión de la médula ósea. La supresión excesiva del sistema inmunitario aumenta la vulnerabilidad a las infecciones, incluyendo infecciones oportunistas, infecciones mortales y sepsis (ver sección 4.8). Se debe monitorizar a los pacientes en tratamiento con CellCept debido a la neutropenia, la cual podría estar relacionada con el propio CellCept, con medicamentos concomitantes, con infecciones virales, o con la combinación de estas causas. En los pacientes tratados con CellCept se deben realizar hemogramas completos una vez por semana durante el primer mes, dos veces al mes durante los meses segundo y tercero de tratamiento y, a continuación, una vez al mes durante todo el resto del primer año. Se debería interrumpir o finalizar el tratamiento con CellCept si se desarrollase la neutropenia (recuento absoluto de neutrófilos < 1,3 x 10³/microlitro). Se debe informar a los pacientes que durante el tratamiento con CellCept las vacunaciones pueden ser menos eficaces y que se debe evitar el empleo de vacunas atenuadas de organismos vivos (ver sección 4.5).Se debe considerar la vacunación contra la gripe. El médico deberá observar las directrices nacionales para la vacunación contra la gripe. Se ha relacionado CellCept con un aumento en la incidencia de eventos adversos en el aparato digestivo, entre los que se incluyen casos poco frecuentes de ulceraciones en el tracto gastrointestinal, hemorragias y perforaciones. Por este motivo CellCept debe administrarse con precaución en pacientes con enfermedad activa grave del aparato digestivo. CellCept es un inhibidor de la inosin monofosfato deshidrogenasa (IMPDH). Por lo que, en teoría, debe evitarse su empleo en pacientes con deficiencia hereditaria rara de la hipoxantina-guanina fosforribosil transferasa (HGPRT) como es el caso de los Síndromes de Lesch-Nyhan y KelleySeegmiller. No se recomienda administrar CellCept al mismo tiempo que azatioprina, ya que su administración concomitante no se ha estudiado.Teniendo en cuenta la reducción significativa del AUC del MPA que produce la colestiramina, la administración concomitante de CellCept y medicamentos que interfieran en la recirculación enterohepática debe llevarse a cabo con precaución, dada la posibilidad de que disminuya la eficacia de CellCept. No se ha establecido el balance beneficio-riesgo de micofenolato mofetilo en combinación con tacrolimus o sirolimus (ver también sección 4.5). 4.5. Interacción con otros medicamentos y otras formas de interacción. Los estudios de interacciones se han realizado sólo en adultos. Aciclovir: se observaron concentraciones plasmáticas de aciclovir más altas cuando se administra con micofenolato mofetilo que cuando se administra aciclovir solo. Los cambios en la farmacocinética del MPAG (el glucurónido fenólico del MPA) fueron mínimos (aumento del MPAG entorno al 8 %) y no se consideran clínicamente significativos. Dado que las concentraciones plasmáticas de MPAG y aciclovir aumentan cuando está deteriorada la función renal, existe la posibilidad de que micofenolato mofetilo y aciclovir, o sus profármacos, ej. valaciclovir compitan en la secreción tubular y se eleve aún más la concentración de ambas sustancias. Antiácidos con hidróxidos de magnesio y aluminio: la absorción del micofenolato mofetilo disminuyó tras su administración con antiácidos. Colestiramina: tras la administración de una dosis única de 1,5 g de micofenolato mofetilo a sujetos sanos tratados previamente con 4 g de colestiramina, tres veces al día, durante 4 días, se observó la disminución del AUC del MPA (ver secciones 4.4, y 5.2). Se deberá tener precaución cuando se administren conjuntamente, debido a su potencial para reducir la eficacia de CellCept. Medicamentos que interfieren con la circulación enterohepática: se debe tener precaución cuando se empleen medicamentos que interfieran con la circulación enterohepática debido a su potencial para reducir la eficacia de CellCept. Ciclosporina A: la farmacocinética de la ciclosporina A (CsA) no experimenta variaciones debidas a micofenolato mofetilo. Sin embargo, si se cesa la administración concomitante de ciclosporina, es previsible un aumento del AUC del MPA entorno al 30%. Ganciclovir: teniendo en cuenta los resultados de un estudio de administración de dosis única a las dosis recomendadas de micofenolato oral y ganciclovir intravenoso, así como los conocidos efectos de la insuficiencia renal en la farmacocinética del CellCept (ver sección 4.2) y del ganciclovir, se prevé que la administración conjunta de estos fármacos (que compiten por los mismos mecanismos de la secreción tubular renal) de lugar a un aumento de la concentración del MPAG y del ganciclovir. Como no hay indicios de que se produzca una alteración sustancial de la farmacocinética del MPA no es necesario ajustar la dosis de CellCept. Se debería considerar las recomendaciones de dosis de ganciclovir, así como llevar a cabo una estrecha vigilancia en aquellos pacientes con insuficiencia renal y que estén siendo tratados con CellCept y ganciclovir simultáneamente o sus profármacos, ej. valganciclovir. Anticonceptivos orales: la farmacocinética y la farmacodinamia de los anticonceptivos orales no se vieron modificadas por la administración simultánea de CellCept (ver

además sección 5.2). Rifampicina: En pacientes no tratados con ciclosporina, la administración concomitante de Cellcept y rifampicina dió lugar a una disminución en la exposición al MPA del 18% al 70% (AUC 0-12h). Por lo tanto, se recomienda vigilar los niveles de exposición al MPA y ajustar las dosis de CellCept en consecuencia para mantener la eficacia clínica cuando se administra rifampicina de forma concomitante. Sirolimus: en pacientes sometidos a trasplante renal, la administración concomitante de Cellcept con ciclosporina redujo la exposición al MPA en un 30-50% en comparación con los pacientes que habían recibido la combinación de sirolimus y dosis similares de Cellcept (ver además sección 4.4). Sevelamer: la administración concomitante de Cellcept con sevelamer disminuyó la Cmax del MPA y del AUC 0-12 en un 30% y 25%, respectivamente, sin consecuencias clínicas (ej: rechazo del injerto). Sin embargo, se recomendó administrar Cellcept al menos una hora antes o tres horas después del uso de sevelamer para minimizar el impacto sobre la absorción del MPA. Con respecto a los ligantes de fosfasto solo existen datos de Cellcept con sevelamer. Trimetoprim/sulfametoxazol: no se observó ningún efecto sobre la biodisponibilidad del MPA. Norfloxacino y metronidazol: no se ha observado interacción significativa en la administración concomitante separada de Cellcept con norfloxacina o con metronidazol en voluntarios sanos. Sin embargo, norfloxacina y metronidazol combinados redujeron la exposición al MPA en aproximadamente un 30% tras una dosis única de Cellcept. Tacrolimus: En los pacientes sometidos a trasplante hepático que comenzaron con Cellcept y tacrolimus, el AUC y la Cmáx del MPA no se vieron afectados de forma significativa por la administración conjunta con tacrolimus. Por el contrario, hubo un aumento de aproximadamente un 20% en el AUC de tacrolimus cuando se administraron dosis múltiples de Cellcept (1,5 g dos veces al día) a pacientes tratados con tacrolimus. Sin embargo, en pacientes con transplante renal, la concentración de tacrolimus no pareció verse alterada por Cellcept (ver además sección 4.4). Otras interacciones: la administración conjunta de probenecid y micofenolato mofetilo en mono eleva al triple el valor del AUC del MPAG. En consecuencia, otras sustancias con secreción tubular renal pueden competir con el MPAG y provocar así un aumento de las concentraciones plasmáticas del MPAG o de la otra sustancia sujeta a secreción tubular. Vacunas de organismos vivos: las vacunas de organismos vivos no deben administrarse a pacientes con una respuesta inmune deteriorada. La respuesta de anticuerpos a otras vacunas puede verse disminuida. (ver también sección 4.4).4.6 Embarazo y lactancia. Se recomienda no iniciar tratamiento con CellCept hasta disponer de una prueba de embarazo negativa. Se debe utilizar un tratamiento anticonceptivo efectivo antes de comenzar el tratamiento, a lo largo del mismo, y durante las seis semanas siguientes a la terminación del tratamiento con CellCept (ver sección 4.5). Debe indicarse a los pacientes que consulten inmediatamente a su médico en caso de quedar embarazadas. No se recomienda el uso de CellCept durante el embarazo, quedando reservado solo para aquellos casos en los que no haya disponible un tratamiento alternativo más adecuado. CellCept solo se debería usar durante el embarazo si el beneficio para la madre supera el riesgo potencial para el feto. Se dispone de datos limitados del uso de CellCept en mujeres embarazadas. No obstante, se han notificado casos de malformaciones congénitas en hijos de pacientes tratados durante el embarazo con Cellcept en combinación con otros inmunosupresores, incluyendo malformaciones en oidos, p.ej. carencia del oído externo/medio o con anomalía en la formación. Los estudios en animales han mostrado toxicidad reproductiva (ver sección 5.3). Se desconoce el riesgo potencial para humanos. En ratas lactantes se ha demostrado que el micofenolato mofetilo se elimina en la leche. No se sabe si esta sustancia se elimina en la leche humana. CellCept está contraindicado en mujeres durante el periodo de lactancia, debido al riesgo potencial de reacciones adversas graves al micofenolato mofetilo en niños lactantes (ver sección 4.3). 4.7 Efectos sobre la capacidad para conducir y utilizar máquinas. No se han realizado estudios sobre la capacidad para conducir y utilizar máquinas. El perfil farmacodinámico y las reacciones adversas descritas indican que es improbable tal efecto. 4.8 Reacciones adversas. Entre las siguientes reacciones adversas se incluyen las reacciones adversas ocurridas durante los ensayos clínicos: Las principales reacciones adversas, asociadas a la administración de CellCept en combinación con ciclosporina y corticosteroides, consisten en diarrea, leucopenia, sepsis y vómitos; se han observado, además, indicios de una frecuencia más alta de ciertos tipos de infección (ver sección 4.4). Neoplasias malignos: Los pacientes bajo tratamiento inmunosupresor con asociaciones de medicamentos, que incluyen CellCept tienen mayor riesgo de desarrollar linfomas y otras neoplasias malignas, principalmente en la piel (ver sección 4.4). Se desarrollaron enfermedades linfoproliferativas o linfomas en el 0,6 % de los pacientes que recibían CellCept (2 g ó 3 g diarios) en combinación con otros inmunosupresores, en ensayos clínicos controlados de pacientes con transplante renal (datos con 2 g), cardíaco y hepático, a los que se les hizo seguimiento durante por lo menos 1 año. Se observó cáncer de piel, excluyendo al melanoma, en el 3,6 % de los pacientes; se observaron otros tipos de neoplasias malignas en el 1,1 % de los pacientes. Los datos de seguridad a tres años en pacientes con transplante renal y cardíaco no mostraron ningún cambio inesperado en la incidencia de neoplasias malignas en comparación con los datos a 1 año. El seguimiento de los pacientes con transplante hepático fue de al menos 1 año pero inferior a 3 años. Infecciones oportunistas: Todos los pacientes transplantados tienen mayor riesgo de padecer infecciones oportunistas, este riesgo aumenta con la carga inmunosupresora total (ver sección 4.4). Las infecciones oportunistas más comunes en pacientes tratados con CellCept (2 g ó 3 g diarios) juntos con otros inmunosupresores, detectadas en los ensayos clínicos controlados de pacientes con transplante renal (datos con 2 g), cardíaco y hepático, a los que se les hizo un seguimiento de al menos 1 año, fueron candida mucocutánea, viremia/síndrome por CMV y Herpes simplex. La proporción de pacientes con viremia/síndrome por CMV fue del 13,5 %. Niños y adolescentes (entre 2 y 18 años): En un ensayo clínico, que incluía a 92 pacientes pediátricos de edades comprendidas entre los 2 y los 18 años, tratados dos veces al día con 600 mg/m2 de micofenolato mofetilo administrado por vía oral, el tipo y la frecuencia de las reacciones adversas fueron, por lo general, similares a aquellas observadas en pacientes adultos tratados con 1 g de CellCept dos veces al día. No obstante, las siguientes reacciones adversas relacionadas con el tratamiento fueron más frecuentes en la población pediátrica, particularmente en niños menores de 6 años de edad, que en la de adultos: diarreas, sepsis, leucopenia, anemia e infección. Pacientes ancianos (* 65 años): Los pacientes ancianos (* 65 años) en general pueden presentar mayor riesgo de reacciones adversas debido a la inmunosupresión. Los pacientes ancianos, que reciben CellCept como parte de un régimen inmunosupresor en combinación, podrían tener mayor riesgo de padecer ciertas infecciones (incluyendo la enfermedad hística invasiva por citomegalovirus), posibles hemorragias gastrointestinales y edema pulmonar, en comparación con individuos jóvenes. Otras reacciones adversas: En la siguiente tabla se indican las reacciones adversas, probablemente o posiblemente relacionadas con CellCept, notificadas en *1/10 y en *1/100 a

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