r 2009 John Wiley & Sons A/S
`
`Transplant Infectious Disease . ISSN 1398 -2273
`
`Review article
`
`Mycophenolate mofetil: e¡ects on cellular immune
`subsets, infectious complications, and antimicrobial
`activity
`
`M.L. Ritter, L. Pirofski. Mycophenolate mofetil: e¡ects on cellular
`immune subsets, infectious complications, and antimicrobial activity.
`Transpl Infect Dis 2009: 11: 290^297. All rights reserved
`
`Abstract : Mycophenolate mofetil (MMF) is one of the most frequently
`used immunosuppressive drugs in solid organ transplant recipients.
`MMF is an inhibitor of inosine-5 0 -monophosphate, and is able to
`preferentially inhibit B-cell and T-cell function. The
`immunosuppressive abilities of MMF have made it one of the most
`successful anti-rejection drugs in transplant patients, but patients also
`appear to have increased susceptibility to infections, speci¢cally
`cytomegalovirus and BK virus. Despite its association with an
`increased risk of infection, MMF has also exhibited antimicrobial
`activity against pathogens including hepatitis C, Pneumocystis jirovecii,
`and human immunode¢ciency virus. A thorough understanding of the
`functions of MMF on the immune system and interaction with
`infectious pathogens could be helpful in implementing preventative
`strategies against opportunistic infections in transplant patients.
`
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`M.L. Ritter1, L. Pirofski1,2
`1Department of Medicine, Division of Infectious Diseases,
`Albert Einstein College of Medicine and Montefiore Medical
`Center, Bronx, New York, USA, 2Department of Microbiology
`and Immunology, Albert Einstein College of Medicine, Bronx,
`New York, USA
`
`Key words: mycophenolate mofetil; solid organ transplant;
`cytomegalovirus; BK virus
`
`Correspondence to:
`Liise-Anne Pirofski, MD, Division of Infectious Diseases,
`Albert Einstein College of Medicine, Room 709 Forchheimer
`Bldg., 1300 Morris Park Avenue, Bronx, NY 10461, USA
`E-mail: pirofski@aecom.yu.edu
`
`Received 29 December 2008, revised 10 February and
`4 March 2009, accepted for publication 5 March 2009
`
`DOI: 10.1111/j.1399-3062.2009.00407.x
`Transpl Infect Dis 2009: 11: 290–297
`
`Mycophenolate mofetil (MMF) is a morpholinoethyl ester
`and a prodrug of mycophenolic acid (MPA), a potent inhib-
`itor of inosine-5 0 -monophosphate dehydrogenase (IMPDH)
`(1). F|rst approved by the US Food & Drug Administration
`for use in renal transplantation in 1995, MMF has now been
`used for over 10 years as an immunosuppressive agent in
`solid organ transplant recipients (2). According to the Sci-
`enti¢c Registry of Transplant Recipients, currently 86% of
`renal transplant recipients receive MMF as part of their im-
`munosuppressive regimen, most frequently in combina-
`tions with prednisone (Pr) and tacrolimus (Tac) (3). MMF
`is unique among transplant medications in its ability to in-
`hibit both T-lymphocyte and B-lymphocyte activity.
`Its anti-B-lymphocytic activity has been targeted for the
`treatment of rheumatologic disease, and already has
`proven e⁄cacy against lupus nephritis (4, 5). However,
`the broad immunosuppressive abilities that make MMF
`an e⁄cacious drug for transplant and autoimmune dis-
`eases might also enhance the risk of infectious complica-
`tions (6).
`
`Mechanism of action
`
`The development of MMF as an immunosuppressive agent
`stemmed from observations in patients with 2 genetic ill-
`nesses. Children with an absence of adenosine deaminase,
`an enzyme responsible for the de novo production of guano-
`sine monophosphate, had a combined immunode¢ciency
`involving de¢ciencies in both T and B lymphocytes (7 ).
`However, children born with Lesch^Nyhan syndrome, a de-
`¢ciency of hypoxanthine-guanine phosphoribosyl trans-
`ferase, and thus the salvage production of guanosine mono-
`phosphate, su¡ered from neurologic abnormalities and
`gout, but had normal immune function (8). These 2 obser-
`vations led scientists to look for an inhibitor speci¢c for de
`novo guanosine monophosphate synthesis. MPA, a fermen-
`tation product of Penicillium brevicompactum and related
`fungi, is an inhibitor of IMPDH, and preferentially inhibits
`de novo guanosine synthesis. Depletion of de novo guano-
`sine causes a lack of deoxyguanosine triphosphate, sup-
`
`290
`
`

`

`pressing DNA synthesis and proliferation of T and B lym-
`phocytes (9). An advantage of MPA is its preferential inhi-
`bition of the type II isoform of IMPDH. The type II isoform
`is expressed almost exclusively in activated T and B lym-
`phocytes, while the type I isoform is expressed in most
`other cells. Therefore, the activity of MPA is speci¢cally
`targeted toward T and B lymphocytes (10, 11). MMF is the
`ester prodrug of MPA, and was found to increase oral bio-
`availability of the drug (12). Most studies have looked at the
`function and e¡ects speci¢cally of MPA on immune cells.
`However, because MMF is metabolized in vivo to MPA, no
`di¡erence in immune activity is expected. MMF has now
`become one of the most frequent medications given to pa-
`tients post transplant, and has proved extremely e⁄ca-
`cious in preventing graft rejection.
`
`Activity against T lymphocytes
`
`MPA inhibits T-lymphocyte proliferation by decreasing
`de novo guanosine production and ultimately DNA synthe-
`sis inT lymphocytes. MPA has also been shown to increase
`apoptosis in human T lymphocytes, speci¢cally in acti-
`vated T lymphocytes (9). This was demonstrated by Nak-
`amura et al. (13) when peripheral blood T lymphocytes
`stimulated with staphylococcal enterotoxin B and treated
`with MPA, showed a marked increase in apoptosis.
`Their ¢ndings suggested that MMF can induce apoptosis
`in antigen-activated T lymphocytes (13). Cohn et al. (14)
`also found that MPA increased apoptosis of activated
`T cells, speci¢cally MOLT- 4 cells, a human T-lymphocyte
`cell line derived from a patient with acute lymphoblastic
`leukemia.
`Studies have also examined the e¡ects of MPA on cyto-
`toxic T cells, mostly in an e¡ort to understand the e¡ec-
`tiveness of MPA in preventing transplant rejection. Eugui
`et al. (15) showed that MPA exhibited a dose-dependent de-
`crease in cytotoxic T-cell activity in mice.
`
`Activity against B lymphocytes
`
`As with T lymphocytes, MPA inhibits B lymphocytes via
`inhibition of IMPDH, and thus DNA synthesis in B lym-
`phocytes. In addition, in vitro studies have shown that
`MPA inhibits the proliferation of human B lymphocytes
`and immunoglobulin (Ig) production in response to Staph-
`ylococcus protein A-sepharose (10). Jonsson and Carlsten (16)
`demonstrated that when a B-cell hybridoma was exposed
`to MPA, a decrease in IgG production occurred, as well as
`a decrease in cytokine levels and decreased proliferation of
`the cells.
`
`Ritter & Pirofski: Mycophenolate mofetil
`
`In animal studies, MPA was ¢rst shown to inhibit anti-
`body formation in rats immunized with sheep red blood
`cells (15). Subsequent studies found that MPA inhibited an-
`tibody production in response to in£uenza virus hemag-
`glutinin in mice (9). Kimball et al. (17 ) found that when
`mice treated with equine-derived polyclonal antithymocyte
`immunoglobulin (ATGAM) received MMF, they had a sig-
`ni¢cant decrease in the production of anti-ATGAM anti-
`bodies.
`More recent literature suggests a reduction in pathogen-
`speci¢c Ig production in patients receiving MMF. Zmonar-
`ski et al. (18) studied 33 renal transplant patients who were
`found to have clinical cytomegalovirus (CMV) disease
`while on immunosuppression with 1 of 3 regimens: azathi-
`oprine (Aza) 1 cyclosporine (CyA) 1 Pr, or MMF 1 CyA 1
`Pr, or Tac 1 MMF. The authors found no di¡erence in CMV
`IgG levels between the patients on di¡erent regimens, but
`there was a decrease in CMV IgM production in the pa-
`tients receiving MMF (18).
`
`Other immunosuppressive activity
`
`MPA has also been shown in vivo to inhibit the capacity of
`dendritic cells to e⁄ciently present antigens to T lympho-
`cytes (19). MPA reduces the recruitment of monocytes into
`sites of graft rejection and in£ammation, and also in-
`creases apoptosis of monocytes (9). Studies also have found
`that MPA directly in£uences the function of endothelial
`cells, speci¢cally disrupting leukocyte adhesion. In addi-
`tion, the recruitment of lymphocytes and monocytes into
`in£ammatory tissues is decreased by MPA (9).
`
`Infectious complications associated with
`MMF
`
`Infection in the post-transplantation period is a major
`cause of patient morbidity and is the most frequent cause
`of death of patients in the early post-transplant period (20).
`While the suppressive activity of MPA on multiple immune
`cell types results in decreased rates of transplant rejection,
`which is bene¢cial, it also dampens the normal immune re-
`sponse to infectious agents, which is detrimental. Pour-
`farziani et al. (21) performed a retrospective cohort study
`of patient and graft survival and causes of post-transplant
`admissions in renal transplant recipients who received ei-
`ther Aza or MMF as part of their immunosuppressive regi-
`men. Their results showed that patient and graft survival
`rates were higher in patients who received MMF rather
`than Aza, and that rates of re-hospitalization for rejection
`
`Transplant Infectious Disease 2009: 11: 290^297
`
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`

`Ritter & Pirofski: Mycophenolate mofetil
`
`were lower in MMF recipients. However, the rate of re-hos-
`pitalization for infection was signi¢cantly higher in pa-
`tients who received MMF (50% versus 37%; P 5 0.002),
`though neither the sites of infection nor the speci¢c patho-
`gens involved were described. The authors also found a
`small increase in mortality and intensive care unit admis-
`sions in the MMF cohort (21).
`Another study demonstrated that late introduction of
`MMF, 41 year post transplant, resulted in increased rates
`of infection.Thirty patients receiving a regimen of prednis-
`olone, Cya, and Aza post transplant were switched from
`Aza to MMF. The rate of infection increased signi¢cantly
`in patients after they were switched to MMF, with a pre-
`conversion rate of 26.7% and a post-conversion rate of
`66.6% (Po0.0005). Most post-conversion infections were
`upper respiratory tract infections (Haemophilus in£uenzae
`or Staphylococcus aureus in most cases, with 1 episode of
`Moraxella catarrhalis), followed by urinary tract infections
`(mostly Escherichia coli or Klebsiella species), 1 case of septic
`arthritis with Streptococcus pneumoniae, and 1 case of
`S. pneumoniae septicemia. All infections except 1 occurred
`41 month after the patient was switched to MMF. The rate
`of recurrent infection also increased signi¢cantly post con-
`version to MMF, with a rate of 6.6% before conversion to
`MMF and 43.3% post conversion (Po0.0005). The authors
`suggest that a possible contributing factor was decreased
`renal function post transplant, essentially increasing se-
`rum levels of MMF with standard doses (6).
`
`CMV
`
`The infectious complication most frequently associated
`with MMF is CMV disease. During the initial trials of
`MMF in transplant patients, MMF was associated with an
`increased rate of CMV disease. The US Renal Transplant
`Mycophenolate Mofetil Study Group, in a comparison of pa-
`tients treated with MMF versus Aza, found a dose-depen-
`dent increase in tissue invasive CMV disease with MMF
`versus Aza (10.8% at 3 g/day and 9.1% at 2 g/day versus
`6.1% with Aza), but no statistical analysis was presented
`(22).
`Moreso et al. (23) also found a dose-dependent increased
`rate of CMV disease in patients receiving MMF. In their
`study, patients who received high-dose Pr with Cya and
`MMF at 3 g/day had a very high incidence of CMV dis-
`ease. But if either the Pr or Cya dose was decreased, or if
`the MMF dose was decreased to 2 g/day, the incidence of
`CMV disease decreased (23). However, use of ganciclovir
`prophylaxis in these study populations was not disclosed.
`In 2004,Wang et al. (24) reviewed randomized clinical trials
`in which patients received either Aza or MMF as part of
`
`292
`
`Transplant Infectious Disease 2009: 11: 290^297
`
`their regimen. They looked at a total of 20 trials with 6870
`patients who had undergone renal transplantation. They
`found a statistically signi¢cant increase in CMV disease
`in patients receiving 3 g/day of MMF versus Aza. While
`there was also an increase in CMV disease in patients re-
`ceiving 2 g/day of MMF, the di¡erence was not statistically
`signi¢cant (24). However, several other studies have also
`demonstrated an increased rate of CMV disease in patients
`on MMF at the recommended dose of 2 g/day (25^28). Jorge
`et al. (2) retrospectively examined the outcomes of the 280
`renal transplants performed over a 10 -year period. While
`MMF was successful in reducing early acute rejection and
`prolonging graft survival, there was a signi¢cantly higher
`rate of CMV disease in patients receiving MMF at the stan-
`dard dose of 2 g/day versus Aza (2). A caveat in evaluating
`these studies is that in all 3, the use of ganciclovir prophy-
`laxis was not noted. In both the Moreso and the Wang stud-
`ies (23, 24), MMF was associated with a statistically
`signi¢cant increase in leukopenia, especially at the higher
`dose of 3 g/day. Hence, it remains unclear whether the in-
`crease in CMV disease was secondary to increased leu-
`kopenia, or due to a direct action of MMF itself.
`A recent study by the RESITRA network of the Spanish
`study group of infection in transplantation, which reported
`on the development of CMVdisease after renal transplanta-
`tion, did not list MMF among the risk factors (29). This
`study had the advantage of being very large (1470 renal
`transplant patients) and prospective. CMV disease oc-
`curred in 6.7% of patients, and after univariate and multi-
`variate analyses, the factors independently associated with
`a statistically signi¢cant increase in CMVdisease included
`donor age 460, Cya use, and chronic graft dysfunction.
`However, it is important to note that an analysis of the e¡ect
`of MMFon CMV risk would have been di⁄cult to ascertain,
`because a majority of the study patients (83.7%) received
`MMF as part of their post-transplant immunosuppressive
`regimen. Along the same lines, it is also noteworthy that
`use of sirolimus was associated with a decreased incidence
`of CMV disease, and that there was a statistically signi¢-
`cant decrease in the use of MMF in patients who were tak-
`ing sirolimus. Therefore, although the RESITRA study is
`important for advancing our knowledge of risk factors for
`CMV disease, it does not directly address the question of
`CMV disease as it pertains to MMF use.
`Zmonarski et al. (18) found that patients with CMV
`disease who were receiving MMF had decreased levels of
`serum anti-CMV IgM compared with patients who were re-
`ceiving Aza. In this study, 75 patients who underwent renal
`transplantation were monitored for the presence of CMV
`pp65 antigen. If the patient became pp65 -positive 1^5
`months post transplant, they were enrolled in the study. Se-
`rum CMV IgG and IgM levels were measured at the time of
`transplantation, 1^5 months after transplantation, and at
`
`

`

`the time of diagnosis of CMV disease. While no di¡erence
`was found in CMV IgG levels in patients receiving regi-
`mens containing MMF versus Aza, there were statistically
`signi¢cant lower levels of IgM in the patients receiving reg-
`imens with MMF. Zmonarski et al. (18) suggest that de-
`creased CMV IgM may have important clinical signi-
`¢cance, as it may correlate with more severe CMV disease.
`Unfortunately the study was very small, with a total enroll-
`ment of 33 patients. A retrospective study by Hardwick et
`al. (30) speci¢cally examined CMV IgG levels in renal
`transplant recipients who received either Aza or MMF and
`developed CMV disease. They reviewed serum CMV IgG
`antibody levels as determined by enzyme immunoassay
`(drawn approximately 1 month after transplantation), and
`found no di¡erence between the level of CMV IgG in pa-
`tients on MMF versus Aza (30). As in the Zmonarski study
`(18), the authors did not ¢nd a decrease in CMV IgG in pa-
`tients receiving MMF, but they did not examine CMV IgM
`levels. The underlying vulnerability of patients on MMF to
`CMV disease has yet to be thoroughly understood, but
`these studies raise the possibility that CMV IgM levels
`may correlate with the risk of CMV disease in patients re-
`ceiving MMF.
`Although CMVdisease may occur more often in those pa-
`tients who are on MMF, MMF-treated patients tend to have
`better outcomes with CMV. This is believed to be due to a
`synergistic e¡ect of MMF on ganciclovir (31). In a study by
`Giral et al. (32), patients with CMV disease receiving MMF
`had less CMV disease-associated graft loss than patients
`receiving Aza. Hence, although the incidence of CMV dis-
`ease may be higher in patients with MMF, once ganciclovir
`is started, patient outcomes tend to improve. Future studies
`may consider investigating at what point to start gan-
`ciclovir therapy in patients receiving MMF and whether
`preemptive or prophylactic ganciclovir may be safer in this
`more vulnerable population.
`
`Ritter & Pirofski: Mycophenolate mofetil
`
`patients and found that of the patients with BKVN, 6 of
`the 7 were on highly immunosuppressive regimens that in-
`cluded Tac and/or MMF. Shi et al. (38) studied 7 cases of
`BKVN in 80 renal transplant recipients and found that a
`signi¢cantly higher number of patients who developed
`BKVN had been on Tac and MMF. Upon histological exam-
`ination, all of the patients who had severe BKVN had been
`receiving Tac and MMF. In addition, all graft failures oc-
`curred in patients on MMF and Tac (38). F|nally, Barton et
`al. (39) found that MMF use was an independent risk factor
`for development of BK viruria in non-renal solid organ
`transplant recipients. In 34 non-renal solid organ trans-
`plant (lung, liver, heart, heart-lung) patients with chronic
`renal dysfunction, 5 had BKV viruria, all of whom were re-
`ceiving MMF (5 of 19 [26%] versus 0 of 15 who were not;
`P 5 0.03) (39).
`While agents such as cidofovir and le£unomide have
`been investigated as possible therapies for BKVN, at this
`time the standard treatment is reduction in or removal of
`immunosuppression, which again emphasizes the essen-
`tial role that immunosuppressive drugs play in the develop-
`ment of BKVN (40).
`
`Other infections associated with MMF
`
`MMF use has also been associated with increased suscep-
`tibility to varicella disease. Lauzurica et al. (40) published 4
`case reports of disseminated varicella among 275 renal
`transplant recipients. The authors noted that, before the
`initiation of MMF, they had never seen a case of varicella
`in their transplant recipients. However, other studies have
`not found a signi¢cant association (41).
`Meier-Kriesche et al. (27 ) found a statistically signi¢cant
`increase in fungal infections in their geriatric renal trans-
`plant population receiving MMF versus Aza, but the spe-
`ci¢c organisms and sites of infection were not reported.
`
`BKV
`
`BKV infection has emerged as an especially important in-
`fection in the transplant recipient. BK virus nephropathy
`(BKVN) has been associated with allograft dysfunction
`and graft failure in 1^8% of renal transplant recipients,
`with a loss of the allograft occurring in half the cases (33^
`35).
`BKV viremia has been associated with the use of higher
`dose immunosuppressive regimens (36). Several studies
`have shown that regimens that include MMF with Tac in-
`crease the incidence of BKV viremia. Mengel et al. (37 ) ex-
`amined 1276 renal biopsies from 638 renal transplant
`
`Possible antimicrobial activity of MMF
`
`Interestingly, while MMF is associated with an increased
`risk of infection, published reports suggest that it may have
`antimicrobial e¡ects against certain pathogens (Table 1)
`(42^52). The ¢rst published reports of the antimicrobial
`properties of mycophenolate were published in the 1960s
`when in vitro studies showed inhibition of vaccinia virus,
`herpes simplex virus, Coxsackie virus, and in£uenza virus
`by MMF (53, 54). Since that time, studies have identi¢ed
`other infections inhibited by MMF.
`
`Transplant Infectious Disease 2009: 11: 290^297
`
`293
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`

`Ritter & Pirofski: Mycophenolate mofetil
`
`The e¡ects of mycophenolate mofetil (MMF) on select infections
`
`Related studies
`
`Pathogen
`
`Author (year), reference
`
`Findings
`
`Proposed mechanism of action
`
`Dengue virus
`
`Diamond et al. (2002 ),
`
`In vitro, MPA blocked DV infection of hepatoma cell lines
`
`MPA prevents the synthesis and
`
`(DV)
`
`(42 )
`
`by 99%
`
`accumulation of DV RNA
`
`Takhampunya et al.
`
`(2006 ), (43 )
`
`In vitro, MPA resulted in a ¢vefold increase in defective DV
`RNA production in monkey kidney cells
`
`MPA depletes intracellular GTP pool,
`
`inhibiting DV RNA production and viral
`
`replication
`
`Hepatitis C
`
`virus (HCV)
`
`Hepatitis B
`
`virus (HBV)
`
`Henry et al. (2006), (44)
`
`In vitro HCV-replication model with a luciferase reporter
`
`Unknown, but appears to be independent
`
`Jain et al. (2002 ), (45)
`
`Randomized clinical trial of patients with HCV undergoing
`
`MMF either has no anti-HCV activity, or its
`
`gener; MPA inhibited HCV replication to 75%; Inhibition
`
`of guanosine depletion
`
`was independent of guanosine production
`
`liver transplant; received either TAC plus prednisone, or
`
`immunosuppressive properties
`
`TAC plus prednisone plus MMF; MMF had no impact on
`
`overwhelm its antiviral e¡ect in the
`
`patients survival, graft survival, rejection, or rate of HCV
`
`clinical setting
`
`recurrence
`
`Wu et al. (2003 ), (46)
`
`In vitro, 2.2.15 cells were treated with di¡erent
`
`MPA suppresses expression of HBsAg
`
`concentrations of MPA. MPA decreased expression of
`
`and HBeAg as well as replication of HBV
`
`HBsAg, HBeAg, and HBV DNA in a dose-dependent
`
`DNA
`
`manner
`
`Ben Ari et al. (2001), (47)
`
`Prospective study of 4 liver allograft recipients with
`
`MMF at the dosage used is not e¡ective
`
`recurrent HBV infection resistant to lamivudine received
`
`at suppressing HBV replication
`
`MMF, in addition to decreased doses of corticosteroid
`
`and cyclosporine. After 8 weeks of therapy, serum ALT
`
`increased in 2 patients, remained stable in 1 patient, and
`
`decreased in 1. Serum HBV DNA levels increased in 3
`
`Pneumocystis
`
`Oz et al. (1997), (48)
`
`Virus-free Sprague^Dawley rats were treated with TAC,
`
`Unclear mechanism by which MMF
`
`jirovecii
`
`sirolimus, dexamethasone, and/or MMF. Increased rates
`
`appears to have antimicrobial action
`
`patients, and decreased in 1
`
`of PCP seen in rats which received TAC, sirolimus, or
`
`against Pneumocystis
`
`dexamethasone, but none of the rats treated with MMF
`
`or MMF plus dexamethasone had PCP
`
`Husain et al. (2002 ), (49)
`
`Combined data from 4 clinical trials where patients
`
`Unclear mechanism by which MMF exerts
`
`received MMF. None of the patients receiving MMF
`
`protection against PCP
`
`developed PCP (0/1068) while 10 of the patients not
`
`receiving MMF developed PCP (1.8%)
`
`Coxsackie
`
`Padalko et al. (2003 ),
`
`C3H-mice were infected with CBV3 and received twice
`
`Unclear, but not believed to be due to
`
`virus B3
`
`(CVB3 )
`
`(50)
`
`daily MMF for 7 days. Mice who received MMF had
`
`inhibition of viral replication since the
`
`signi¢cant reduction in the development of CBV-induced
`
`titers of infectious virus and viral RNA
`
`myocarditis (dose dependent)
`
`were increased in mice treated with MMF
`
`West Nile virus
`
`Morrey et al. (2002 ), (51)
`
`MA-104 cells infected with NewYorkWNV; assays used to
`
`measure inhibition of virus showed MPA to be one of the
`
`most potent antivirals; it was even more active against a
`
`Ugandan strain of WNV
`
`Unclear antiviral activity in vitro against
`WNV
`
`(WNV)
`
`Yellow fever
`
`virus (YFV)
`
`Neyts et al. (1996 ), (52 )
`
`Used the attenuated vaccine strain 17D of YFV to
`
`MPA has anti-YFV activity, but it is not
`
`evaluate inhibitory e¡ect in infected Vero cells. MPA was a
`
`merely cytotoxic, given the lack of activity
`
`strong inhibitor of YFV, but had little or no e¡ect on Bunya
`
`against Bunya virus PuntaToro and HSV
`
`virus PuntaToro or HSV
`
`GTP, guanosine triphosphate; TAC, tacrolimus; MPA, mycophenolic acid; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B virus early antigen;
`
`ALT, alanine aminotransferase; PCP, Pneumocystis jirovecii pneumonia; TAC, tacrolimus; HSV, herpes simplex virus.
`
`Table1
`
`In vitro studies with dengue virus showed that MPA com-
`pletely inhibited infection of human cells by the virus (42,
`43). In patients with chronic hepatitis C virus (HCV) dis-
`ease, MMF was shown to be a potent in vitro inhibitor of
`
`HCV replication. Interestingly, the inhibition was indepen-
`dent of cell proliferation and guanosine depletion, so the
`true mechanism of action is unknown (44). However, a pro-
`spective randomized trial of MMF in liver transplants with
`
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`Transplant Infectious Disease 2009: 11: 290^297
`
`

`

`HCV showed no impact on patient survival, graft survival,
`rejection, or rate of HCV recurrence. The authors suggest
`that while MMF has in vitro activity against HCV, the over-
`all immunosuppressive properties of the drug may domi-
`nate in vivo (45). MMF was also found to have some
`activity against hepatitis B virus in vitro (46), but has not
`been found to be e¡ective in vivo (47 ).
`MMF has been shown to have a possible protective e¡ect
`against Pneumocystis jirovecii pneumonia (PCP) (48, 49).
`This has raised the question of the necessity of PCP pro-
`phylaxis in patients on MMF. Isolated reports suggest
`MMF may also have activity against Coxsackie virus (50),
`West Nile virus (51), and yellow fever virus (52). At this
`point, MMF is not a standard therapy for any of these infec-
`tions.
`F|nally, MMF has demonstrated activity against human
`immunode¢ciency virus (HIV) both in vivo and in vitro (55^
`61). Its role against HIV is somewhat controversial. MPA is
`consistently shown to increase the activity of other antiret-
`rovirals, but it is unclear if MPA alone has e¡ective activ-
`ity against the virus (62, 63). MPA is known to be active
`against HIV especially in combination with abacavir (64,
`65). The mechanism of anti-HIV activity is believed to
`be secondary to guanosine triphosphate depletion, with
`the inhibition of reverse transcriptase, and also through a
`reduction in gp120 expression in transformed cells (66).
`Several studies suggested that MPA may have a role in the
`treatment of multidrug-resistant HIV infection; however,
`clinical trials have failed to show a signi¢cant bene¢t from
`the addition of MMF to anti-retroviral regimens. Sankat-
`sing et al. (55) found that MMF did not signi¢cantly in-
`crease either the plasma HIV-1 RNA decay rate or the
`decay rate of latently infected cells when it was added to a
`triple class antiretroviral regimen in treatment-na|« ve pa-
`tients.
`
`Conclusion
`
`As the use of MMF increases in transplant recipients and
`in autoimmune diseases, it has become more important to
`fully understand its impact on infectious complications.
`Further studies are needed to investigate how the e¡ects
`of MMF on immune cells predispose patients to speci¢c in-
`fections. Such information may make it possible to antici-
`pate the infections, and help determine the choice and
`length of prophylactic antimicrobials in transplant recipi-
`ents receiving MMF.
`In addition, the possible antimicrobial activities of MMF
`could be utilized in sparing patients from unnecessary pro-
`phylaxis, or in guiding the use of MMF in speci¢c popula-
`
`Ritter & Pirofski: Mycophenolate mofetil
`
`tions. For instance, if further studies are able to fully
`decipher the relationship between MMF and PCP, an argu-
`ment could be made for modifying PCP prophylaxis in pa-
`tients receiving MMF. In doing such, patients could be
`spared the possible hematopoietic side e¡ects of trime-
`thoprim-sulfamethoxazole. Given the in vivo activity of
`MMF against HIV, future studies could investigate the pos-
`sible bene¢ts of using MMF in HIV-positive transplant pa-
`tients.
`A better understanding of the activity of MMF against
`these infections could bene¢t future transplant recipients
`and improve the overall outcomes of patients in the post-
`transplant period.
`
`Acknowledgement:
`
`This work was supported by grants from National Insti-
`tutes of Health Grants R01AI045459 and R01AI035370
`to L.P.
`
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