www.elsevier.com/locate/trre

Transplantation Rev

Tailoring immunosuppressants to hepatitis C virus–infected

transplant patientsB

Spencer Hoovera, Adnan Saida,b, Rob Strikera,4aDepartment of Medicine, University of Wisconsin Medical School, Madison, WI 53706, USA

bDepartment of Medicine Middleton Veterans Hospital, University of Wisconsin Medical School, Madison, WI 53706, USA

Abstract

Hepatitis C virus (HCV) is the leading indication for liver transplant in the world. After transplantation, patients remain infected with

HCV and are at high risk for recurrent end-stage liver disease. We will review retrospective and prospective studies, which suggest that

specific immunosuppressive cocktails are more associated with severe recurrent HCVand relate these studies to in vitro analysis of the effect

of immunosuppressants on HCV in vitro. Immunosuppressive antibodies and high-dose steroids have been associated with increased viral

replication in the short term, and data also suggest worsening liver disease in the long term. On the other hand, mycophenolate mofetil,

azathioprine, and cyclosporine have all been shown to have antiviral properties against HCV in in vitro studies. Although future research is

desperately needed, a picture of how the risks and benefits of immunosuppressive regimens in HCV-infected patients differ from non–HCV-

infected patients is emerging, and possible recipes for immunosuppressant cocktails tailored to limit HCV while still preventing graft

rejection are contemplated.

D 2006 Elsevier Inc. All rights reserved.

1. The problem: HCV is more aggressive in

immunosuppressed patients

Currently, approximately 40% of liver transplants are due

to hepatitis C virus (HCV)–related liver disease. Hepatitis C

virus is common among hemodialysis patients (at least 5%

are viremic in developed countries and much higher

elsewhere), and HCV-positive organs are sometimes used

in urgent situations for HCV recipients [1]. Therefore, HCV

infection is a common issue even in non–liver transplant

patients. Hepatitis C virus recurs in virtually 100% of liver

allografts at the time of transplantation in HCV viremic

recipients. Hepatitis C virus–related liver disease is accel-

erated in immunosuppressed patients including transplant

recipients. Within 1 year after transplantation, 50% of HCV-

infected liver transplant recipients have histologic reoccur-

rence of HCV, and almost 30% are again cirrhotic after

5 years [2]. Consequently, the HCV epidemic is drastically

worsening the shortage of livers.

0955-470X/$ – see front matter D 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.trre.2006.07.002

B R Striker is supported in part by NIH K08AI0557750, and funding

relevant to this review was provided by the University of Wisconsin School

of Medicine and Public Health (Madison, WI) from The Wisconsin

Partnership Fund for a Healthy Future. A Said is supported in part by an

AGA research scholar award.

4 Corresponding author. Tel.: +1 608 262 8418; fax: +1 608 262 4725.

E-mail address: rtstriker@facstaff.wisc.edu (R. Striker).

Both patient and graft survival is decreased in HCV-

positive liver transplant patients compared with HCV-

negative liver transplant patients [3]. There are less

definitive data on the impact of HCV in renal transplant,

but studies suggest that the risks of sepsis- and liver-related

death are both higher in HCV-infected renal transplant

patients than in renal transplant patients without HCV [4]. In

the 1990s, most immunosuppressant trials in liver trans-

plantation focused on demonstrating which regimens had

low rates of rejection. This has now been accomplished.

Given the increased morbidity of HCV-related liver disease,

there is now a clear need to balance the prevention of

allograft rejection with that of limited HCV disease (Fig. 1).

Hepatitis C virus reoccurrence is clearly a complex and

variable event reflecting the interplay among the donor liver,

virus, and recipient immune system, and immunosuppres-

sion is the variable that can be most easily controlled.

Antiviral therapy, which currently consists of some form of

interferon alpha given in combination with ribavirin, is

increasingly being offered to HCV-infected transplant

patients. Therefore, an ideal immunosuppressant regimen

would be one that the patient could take with antivirals with

no loss in prevention of rejection. Unfortunately, the

scientific and clinical trial evidence needed to design

immunosuppressive regimens for HCV-infected patients

iews 20 (2006) 157–164

Fig. 1. The collective potency of an idealized immunosuppressive regimen

would minimize immunosuppressant to avoid recurrent HCV disease

without raising the risk of rejection. Theoretically, specific proviral or

antiviral effects of individual immunosuppressants could alter this balance.

S. Hoover et al. / Transplantation Reviews 20 (2006) 157 – 164158

remains incomplete despite several studies and considerable

clinical experience (Table 1).

2. Retrospective and prospective comparisons of

immunosuppressive regimens in HCV

2.1. Immunosuppressive antibodies

Immunosuppressive antibodies are often used perioper-

atively to deplete circulating lymphocytes and prevent early

Table 1

Summary of selected comparisons of immunosuppressant for HCV-infected trans

Immunosuppressant Ref No. of HCV-infected

patients

Design

Antibodies Sheiner et al [9] 96 Retrosp

Nelson et al [5] 21 Case se

Neuhaus et al [7] 381 Prospec

Random

Washburn et al [65] 8 Prospec

Random

Eason et al [64] 22 Prospec

Random

Steroids Garcia-Retortillo et al [23] 20 Prospec

Gane et al [37] 25 Prospec

Berenguer et al [19] 554 Retrosp

Brillanti et al [25] 80 Retrosp

Antimetabolites Zekry et al [17] 13 Prospec

Crosso

Berenguer et al [19] 554 Retrosp

Bahr et al [21] 130 Retrosp

Samonakis et al [22] 145 Retrosp

Wiesner et al [10] 54 Random

Prospec

Calcineurin

inhibitors

Wiesner [26] 113 Prospec

Firpi et al [57] 115 Retrosp

Levy et al [30] 173 Prospec

Martin et al [29] 79 Prospec

RATG = rabbit antithymoglobin.

rejection while minimizing use of calcineurin inhibitors. In

liver transplantation, this is infrequently done, but these

antibodies are more commonly used to treat steroid-resistant

rejection (SRR). Early studies, including an uncontrolled

trial with the anti–interleukin-2 receptor, anti-CD25 [5],

suggested that induction agents are associated with more

severe disease. Later studies with basiliximab (Simulect;

Novartis, Basel, Switzerland) [6,7] suggested that it could

be used safely in induction, but when muromonab (Johnson

& Johnson, New Brunswick, NJ) was used to treat SRR,

studies have suggested an association with HCV recurrence

on biopsy that is difficult to separate from the steroid

treatment and rejection itself [8,9].

2.2. Antimetabolites (mycophenolate mofetil and

azathioprine)

Both azathioprine (AZA) (Imuran; Glaxo Smith Kline,

Brentford, UK) and mycophenolate mofetil (MMF) (Cell-

Cept; Roche, Basel, Switzerland) inhibit purine synthesis,

though by different mechanisms. Mycophenolate mofetil

alters purine synthesis by inhibiting a key cellular enzyme,

inosine monophosphate dehydrogenase, necessary to main-

tain purine pools in dividing cells. The antiviral ribavirin

also inhibits inosine monophosphate dehydrogenase, and

this shared property has prompted multiple studies aimed at

plant patients

Conclusion

ective OKT3 for SRR-associated sever liver disease, unclear if induction

with OKT3 reduces SRR or promotes worsening liver disease

ries Daclizumab and MMF worsens liver disease

tive Basiliximab; small benefit from less rejection,

most benefit in HCV (�) groupized

tive Daclizumab; no obvious harm 18 mo of follow-up

ized

tive RATG decreases SRR and total steroid use

ized

tive Steroids decrease viral clearance immediately posttransplant

tive Steroid boluses for rejection are associated with increased viremia

ective Long-term steroids and AZA lead to less HCV reoccurrence,

more reoccurrence in MMF induction

ective Slow taper best

tive MMF leads to higher viral loads than AZA

ver

ective Long-term steroids and AZA lead to less HCV reoccurrence,

more reoccurrence in MMF induction

ective AZA-treated HCV-infected patients had less fibrosis

than non–AZA-treated patients

ective AZA-treated HCV-infected patients had less fibrosis

than non–AZA-treated patients

ized MMF is superior in preventing rejection, no difference

in graft survivaltive

tive CsA associated with more rejection and less survival

ective CsA associated with better response to interferon than Tac

tive Better graft and patient survival in CsA arm, but only

6 mo of follow-up, so difference may not be related to HCV

tive No difference, but HCV levels were higher in CsA arm

S. Hoover et al. / Transplantation Reviews 20 (2006) 157 – 164 159

detecting an antiviral effect fromMMF both in nontransplant

HCV-infected patients as well as in HCV-positive transplant

patients. Mycophenolate mofetil has been associated with

less rejection than AZA in liver transplant recipients [10,11];

yet, to date, there is little evidence of a measurable antiviral

effect because of MMF in most transplant or nontransplant

studies with the possible exception of the early peritransplant

setting. Platz et al [12] demonstrated reduced viremia in

HCV-positive transplant recipients after 3 weeks of MMF

therapy for acute rejection. Fasola et al [13] reported the use

of high-dose induction MMF to be associated with reduced

HCV viremia at 3 months and decreased incidence of fibrosis

at 1 year, but the antifibrotic effect was lost at 2 years.

Several studies have actually found increased HCV viremia

and/or elevated transaminase with the use of MMF in renal

[14], cardiac [15], and liver patients [16]. The most direct

comparison of the effect of AZA andMMFwas a prospective

crossover study from AZA to MMF in 13 long-standing liver

transplant recipients [17]. No change in alanine aminotrans-

ferase levels was seen, but the mean viral load increased on

MMF. The increase was partially reversed when patients

were switched back to AZA. Firpi et al [18] reported similar

results, including the slight rise in viremia when using MMF

in nontransplant HCV-infected patients. Any antiviral effect

from MMF seems to be overwhelmed long term by its

immunosuppressive properties. These small prospective

trials are consistent with larger retrospective studies that

look for associations between severe or mild liver disease.

Histologic progression of fibrosis was compared in 1353

liver biopsies from 554 transplant recipients from 4 different

centers. A multivariable analysis suggested that inductions

with MMF and less than 6 months of AZAwere both among

the factors associated with severe disease [19]. Three single-

center series of 65 [20], 130 [21], and 193 [22] liver

transplant patients found that AZA-treated HCV-infected

liver transplant patients had less fibrosis [21], and in the

largest study, AZA [22] was the most protective variable for

death found, even more protective than young donor age. For

solid organ transplantation in general, MMF is clearly

associated with less rejection than regimens using AZA in

the first year of transplantation. Therefore, perhaps in

combination with other agents not associated with worse

outcome in HCV-infected patients, MMF could still play a

useful role.

2.3. Corticosteroids

Several studies have shown that in the immediate

posttransplant period, boluses of steroids to treat rejection

actually increase HCV viremia. One of the first studies to

perform detailed viral kinetics immediately posttransplant

[23] also came to the conclusion that the corticosteroid

containing regimens tended to have an earlier rise in

HCV viremia posttransplant. The main finding of this

small study was that all patients had early viremia

detectable regardless of the immunosuppressive regimen.

A 1-year, placebo-controlled, prospective study comparing

2 immunosuppressive induction regimens, in which one

lacked corticosteroids, found HCV reoccurrence to be

unaffected, but patient and graft survival favored the regimen

lacking corticosteroids [24]. In longer-term studies, the

answer is less clear. Maintenance steroids for greater than

12 months was found to be a protective factor when

compared with shorter courses of corticosteroids [19].

Similarly, abrupt removal of steroids is associated with

histologic worsening of HCV [25].

2.4. Calcineurin inhibitors

The core of almost all immunosuppressant cocktails for

liver transplant recipients is calcineurin inhibition either by

cyclosporine (CsA) (Neoral, Novartis) or tacrolimus (Tac)

(FK506; Astellas Pharma, Tokyo, Japan). Most of the

clinical data generally suggest that there is little difference

in HCV-infected transplant patients that can be attributed to

the type of calcineurin inhibitor used. Early studies are

complicated by higher Tac doses than are currently used,

likely lower liver levels of CsA achieved by the Sandim-

mune formulation of CsA rather than microemulsion (Neo-

ral) used most commonly today, and different secondary

immunosuppressants between the calcineurin inhibition

arms [25]. Nevertheless, 2 large pivotal trials, 1 in the

United States and 1 in Europe, each with HCV-infected

(20%) and HCV-uninfected liver transplant recipients

(~80%), suggested that Tac is associated with less rejection

in liver transplantation than is CsA. Consequently, Tac is

now the predominant calcineurin inhibitor used in liver

transplantation regardless of HCV status [26-28]. Two

recent prospective trials have also shown little difference

between Tac and CsA, although each favored slightly a

different calcineurin inhibitor. Martin et al [29] randomized

79 HCV-infected liver recipients to receive Tac or CsA as

primary immunosuppression posttransplant. The cumulative

probability for HCV recurrence at 1 year was .38 and .54

(Tac vs CsA, P = .19), but CsA-treated patients had

significantly larger increases in HCV RNA. Levy et al [30]

on the other hand randomized 495 liver transplant recipients

to Tac vs CsAwith C2 monitoring, and 85 and 88 patients in

each arm were HCV infected. At 6 months, death or graft

loss was higher in the Tac vs CsA arm (15% vs 6%, P b

.05), but only a portion of this difference was potentially

attributable to recurrent HCV, and any advantage in limiting

recurrent HCV would not be expected with such short

follow-up.

3. Why have clinical studies not given more clear

answers for the optimal immunosuppressive regimen

for an HCV-infected patient yet?

Ideally, long-term studies are needed to address this issue

because recurrent HCV is most commonly a late complica-

tion of transplantation. In the mid-1990s, combined regimen

of CsA, corticosteroids, and AZA was used for approxi-

mately 80% of both liver and kidney recipients, but by

S. Hoover et al. / Transplantation Reviews 20 (2006) 157 – 164160

2002, approximately 80% of patients had the CsA replaced

with Tac [31]. Donor age has also increased, and separating

the influence of age from changing immunosuppressant

regimens is not always possible. Clinical trials of even a few

hundred patients are underpowered to detect differences in

recurrence. It is important to remember that although few

dispute that liver transplant outcomes are worse for HCV, it

required a large study of more than 12000 transplantations

to statistically prove this after many small studies had failed

[3]. This is likely because of variability of patients, donor

grafts, and genetic variability between HCV isolates, even

isolates of the same genotype, rather than the effect of HCV

itself being so small.

4. What is the goal?

Because the pathogenesis of HCV-related liver disease in

the transplant setting is not understood, conceptual strategies

for how to limit HCV recurrence vary. Although most studies

have aimed at comparing and/or minimizing immunosup-

pressants, there are those that favor the idea that immuno-

suppressants actually control a pathologic anti-HCV immune

response. Such an immune response occurs most likely

during immune reconstitution as immunosuppressants are

typically weaned. Because we do not understand pathogen-

esis in a nontransplant host, this is an intriguing, but difficult,

strategy to use. Although there is certainly an evidence of

immune-mediated damage in nontransplant patients, such

mechanisms may vary considerably from the nontransplant

situation when cytotoxic T lymphocytes are non-HLA

mismatched as in a graft. One retrospective study that

invokes this model did have an impressive difference in

recurrent HCV and long-term outcome between 2 groups of

transplant patients [32]. The group with the lower graft

survival (39% at 3 years vs 95%) received antithymocyte

globulin (Pfizer, New York City, NY) in addition to Tac that

was later weaned, whereas the group with the better survival

received Tac continuously with decreasing doses of predni-

sone. The disparity in outcomes was significantly smaller in

2 groups of HCV-negative liver recipients, consistent with

the poor outcome being due to HCV, rather than some other

factor. Of course, these results could also be consistent with

the poor outcomes seen with antilymphocyte antibodies

[5,8,9] rather than the overly aggressive/premature weaning

of immunosuppressants. As antiviral options for HCV

increase, this debate between too much or too little

immunosuppression is likely to fade. The ultimate goal is

eradication of HCV itself, and therefore, as eradication

becomes more attainable, the compatibility of immunosup-

pressants with antivirals becomes the main issue.

5. How much do we gain and how much do we lose if

rejection increases?

Efforts to minimize HCV reoccurrence may be putting

the cart before the horse if they allow repeated episodes of

rejection. Much of the literature associating poor outcomes

with either steroids or immunosuppressive antibodies could

also be interpreted as rejection itself being associated with

HCV recurrence. Hepatitis C virus recurrence correlates

with severe rejection regardless of how it is treated. Sheiner

et al [9] documented that 28 patients with no episodes of

SRR had a low incidence of histologic recurrence of HCV

(18%), recurring 246 days after transplant on average vs

those with 1 episode of SRR (42%), or more than 1 episode

(70%) recurring at 127 days.

6. Modeling the effects of immunosuppressants on HCV

outside the patient

Theoretically, we could learn much about how to optimize

immunosuppressive regimens for HCV-infected patients if

an appropriate model system existed. Unfortunately, the

primary animal model for HCV is the chimpanzee, unlikely

to be used for transplant studies for cost and ethical reasons.

A few immunosuppressed mouse systems exist in which the

mouse liver is humanized or a human hepatoma is given to

the mouse, but because of the immunosuppressive genetic

backgrounds required to allow viral growth, they are

currently unsuitable for studying immunosuppressants.

Hepatitis C virus could not be reliably grown in cell culture

until 2005, when 3 groups [33-35] showed that a genotype 2

isolate from an unusual case of fulminant hepatitis was

competent to grow in human hepatocellular carcinoma cells.

This system was recently used to show that at least the

unusual genotype 2 isolate is sensitive to CsA [36] but

otherwise has not been used to determine if immunosup-

pressants alter HCV directly. This question has been

examined using RNA viruses from the same family

(Flaviviridae) and HCV replicons. Hepatitis C virus repli-

cons are intracellular RNAs whose propagation depends

upon the RNA replication machinery of the HCV nonstruc-

tural proteins. Replicons do not model the very early steps of

viral entry or the late steps of assembly and exit.

Several groups using an HCV replicon have examined

the effect of immunosuppressants on HCV replication in

vitro, and an example of such experiments is shown in

Fig. 2. Such comparisons need to take into account the

relative liver levels of the different drugs whenever possible.

There is no evidence of potentiation by steroids of either

related RNA viruses or HCV replicons in cell culture despite

the clinical experience of Gane et al [37] and Charlton et al

[38], and known in vitro and in vivo potentiation of hepatitis

B virus by steroids [39]. Several studies have shown an

antiviral effect of mycophenolate for various RNA viruses,

and the largest effect of mycophenolate is on viral

translation [40]. These studies used viruses that, like most

cellular messenger RNAs, have cap-dependent translation,

but HCV uses cap-independent translation. Stangl et al [41]

examined antiviral effect of mycophenolate on a bovine

Pestivirus that is closely related to HCV and that also uses

Fig. 2. Immunosuppressants vary in their effect on HCV replication. Human

hepatoma cells derived from the Huh7 cell line stably transfected with a

genotype 1b HCV replicon with a phosphatase reporter marker [66] were

exposed to different concentrations of commonly used immunosuppressants

in cell culture active forms, at pharmacologically relevant doses when

known. Dex indicates dexamethasone; MPA, mycophenolate.

S. Hoover et al. / Transplantation Reviews 20 (2006) 157 – 164 161

cap-independent translation. For that virus, the antiviral

effect was quite small, smaller in fact than the antiviral

effect of AZA. The antiviral effect of AZAwas mediated by

specific thiopurine nucleoside metabolites of AZA and was

equally or more potent than the antiviral effect of ribavirin

against this bovine virus and a genotype 1b HCV replicon,

although in vivo ribavirin accumulates to higher levels in

the serum than do thiopurines [42]. Both for the potential

antiviral effect of AZA, and even for the well-studied

antiviral effect of ribavirin against HCV, the active

metabolite in the liver remains unknown. Presumably, at

least for ribavirin, the active metabolite is ribavirin

triphosphate, which alters viral RNA synthesis. Estimating

average and interpatient variability in triphosphate metab-

olites is difficult.

Studies by 2 groups have shown that 2 different HCV 1b

replicons are inhibited by CsA, but not by Tac. In contrast to

the effect of AZA, the effect of CsA on the replicon is strongly

time dependent. Prolonged exposure of relatively low

concentrations of CsA still results in a cumulative inhibition

[43,44], similar to short exposures at higher concentrations.

Inhibition of the HCV replicon by CsA is dependent on

inhibition of the peptidyl proline isomerase activity of

cyclophilins as opposed to the interaction with calcineurin.

Nonimmunosuppressive analogs of CsA that block the

peptidyl proline isomerase activity of cyclophilins can still

inhibit HCV [45]. Tacrolimus is not a potent inhibitor of

HCV replication like CsA presumably because it inhibits the

peptidyl proline isomerase activity of FK binding proteins

but not that of cyclophilins. The closely related bovine

Pestivirus is also sensitive to CsA although at higher

concentrations than HCV, but not Tac. A replicon from the

2a HCV strain that grows in cell culture (Japanese

Fulminant Hepatitis, JFH1) is not as sensitive as 2 different

1b replicons [36]. Two competing models for how CsA

inhibits HCV have been proposed. One suggests that any

trigger of the unfolded protein response would have the

effect of CsA, and that the antiviral effect of the unfolded

protein response [46] can be mediated by cyclophilin A, B,

or C. The other model is based on evidence that cyclophilins

A and C were not involved, but that cyclophilin B was

localized on both faces of the endoplasmic reticulum

membrane, and the previously unknown cytoplasmic

portion was necessary for the viral polymerase to bind viral

RNA. In binding of cyclophilin B, the polymerase could be

disrupted by specific mutations to the polymerase, but

because none of these mutants were functional, it is

unknown if they confer CsA resistance [47]. Although it

may seem superficially surprising that an immunosuppres-

sant has antiviral properties, it is not unprecedented in the

case of CsA. Cyclosporine inhibition of proline isomerase

activity, particularly cyclophilin A, decreases HIV-1 gag

protein folding and inhibits HIV-1 replication [48]. The

cyclophilin A dependence of HIV-1 is unique among

lentiviruses and is not even shared by the closely related

HIV-2 [49].

7. Cyclosporine as an antiviral, fact or artifact of in vitro

studies

As related above, CsA, unlike Tac, has potent anti-HCV

activity in the replicon model, but to date, there is little

suggestion of this translating into a clinical benefit in

transplantation studies. On the other hand, in vivo CsA

inhibition of HCV is also consistent with a nontransplant

Japanese clinical study in which CsA added to the efficacy

of interferon in HCV treatment [50]. In this prospective

randomized trial, 44 chronic HCV-infected patients treated

with interferon alpha-2b had a 52% end of treatment

response. The 76 patients given the same dose of interferon

alpha-2b and CsA had a 76% end of treatment response

(P = .002). The relapse rate for both arms was high,

perhaps because only 24 weeks of nonpeglyated interferon

therapy was given. The benefit was limited to genotype

1 patients and not genotype 2. Pharmacokinetic parameters

of CsA dosing may be important in this study because it

dosed CsA every 6 hours [50], leading to a more constant

CsA level, whereas the dosing of CsA for organ transplant is

typically every 12 hours. To achieve the levels of CsA

necessary to inhibit HCV may require the known ability of

CsA to concentrate and accumulate in the liver (up to

40-fold) [51,52]. This accumulation has not been well

studied on a population basis and may not occur in every

patient to the extent demonstrated so far [51,52]. The

controlled trial from Japan is consistent with small case

series from Japan/China of CsA-suppressing viremia

[53-55]. None of the transplant trials comparing CsA and

Tac have been performed in regions such as Asia where

genotype 1b is approximately 10-fold more common than

genotype 1a. Both viral genetic variability as well as

pharmacokinetics that are not optimized for an antiviral

effect could easily obscure a small but clinically significant

difference between CsA and Tac in clinical transplant trials.

S. Hoover et al. / Transplantation Reviews 20 (2006) 157 – 164162

Cotler et al [56] examined the effect of CsA and interferon

on HCVon 10 patients and found that only 30% responded,

a percentage similar to that of interferon therapy alone.

Those most likely to respond had CsA trough levels above

200 ng/mL. One possibility is that CsA bmonotherapyQ onlytransiently reduces HCV RNA, until CsA-resistant mutants

arise. By itself, this may be clinically insignificant, but the

mutant virus may be altered in responsiveness to traditional

interferon and ribavirin antiviral therapy. This hypothetical

mechanism would explain higher responsiveness to inter-

feron and ribavirin therapy in CsA than Tac-treated patients

that some have reported [57]. A synergistic effect between

CsA and interferon, as well as optimization of CsA

pharmacodynamics for maximal antiviral effect, was the

rationale for an open-labeled trial in Japan. This trial gave

41 HCV genotype 1b liver transplant patients interferon beta

and CsA for cycles of induction and intensification therapy,

with more conventional interferon alpha and ribavirin

maintenance therapy in between for a total therapy of

approximately 8 months. Cyclosporine serum trough levels

were maintained between 250 and 400 ng/mL. Although

uncontrolled, the study achieved an impressive 66%

sustained virological response [58].

Logistically, it is difficult for transplant trials to be larger

than a few hundred patients (500 largest, most approxi-

mately 200). Few dispute the advantage that ribavirin

provides to the treatment of HCV, but proving this

advantage required trials of approximately 1000 patients

[59,60]. Before this trial, several smaller trials [61-63]

suggested (incorrectly) that there was no direct antiviral

effect of ribavirin. Studies of 100 to 200 patients may be

misleading if not controlled or stratified for viral suscepti-

bility and pharmacokinetics. Of course, this is no substitute

for direct data in transplant patients demonstrating an

advantage of CsA over Tac if there is one. A study designed

to demonstrate such a theoretical benefit would ideally

target patients with viral isolates known to be very

susceptible to CsA, and demonstrate the liver levels of

CsA obtained.

8. Conclusions

Further research is needed to determine the optimal

immunosuppressant cocktail for HCV-infected patients, but

minimizing the overall immunosuppressant effect is more

critical for HCV-infected patients than other transplant

recipients. In general, high-dose pulses of steroids should

be avoided, but the effect of maintenance steroids is still

quite unclear. Long-term use of MMF rather than AZA may

be associated with a small rise in viremia. These general

statements must be tempered by the fact that few studies

have considered whether the effect of immunosuppressants

depends upon the specific HCV strain. Future studies would

benefit from considering the individual effects of immuno-

suppressants on specific strains of HCV.

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