Clinical Infectious Diseases Advance Access published August 20, 2014

MAJOR ARTICLE

HIV/AIDS

Pharmacokinetic Study of Raltegravir in

HIV-Infected Patients With End-Stage Liver
Disease: The LIVERAL-ANRS 148 Study
Caroline Barau,1,2 Josphine Braun,3 Corine Vincent,3 Stphanie Haim-Boukobza,2,4 Jean-Michel Molina,5
Patrick Miailhes,6 Isabelle Fournier,3 Jean-Pierre Aboulker,3 Daniel Vittecoq,2,7 Jean-Charles Duclos-Valle,2,8
Anne-Marie Taburet,1,2 and Elina Teicher2,7; for the Agence Nationale de Recherche sur le Sida et les hpatites (ANRS)
148 Study Groupa
1

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Assistance PubliqueHpitaux de Paris (AP-HP), Hpital Bictre, Service de Pharmacie Clinique et Pharmacocintique, Le Kremlin-Bictre; 2Dpartement
Hospitalo, Universitaire Hepatinov, 3INSERM SC10-US019, and 4AP-HP, Hpital Paul Brousse, Service de Virologie, Villejuif; 5AP-HP, Hpital Saint-Louis,
Service des Maladies Infectieuses et Tropicales et INSERM U941, Universit Paris VII Denis Diderot; 6Hospices Civils de Lyon, Service des Maladies
Infectieuses et Tropicales, Hpital de la Croix-Rousse et INSERM U1052; 7AP-HP, Hpital Bictre, Service de Mdecine Interne et Maladies Infectieuses,
Le Kremlin-Bictre; and 8AP-HP, Hpital Paul Brousse, Centre Hpato-Biliaire et INSERM UMR-S785 Villejuif, France

Background. The end-stage LIVER disease and RALtegravir-Agence Nationale de Recherche sur le Sida et les
hpatites (LIVERAL-ANRS) 148 study aimed to evaluate the safety, efcacy, and pharmacokinetic parameters of
raltegravir (RAL) in human immunodeciency virus (HIV)infected patients with end-stage liver disease (ESLD)
(substudy 1) and to assess the lack of pharmacokinetic interaction between RAL and the immunosuppressive regimen introduced after liver transplant (substudy 2).
Methods. All patients received 400 mg RAL twice daily plus 2 nucleoside reverse transcriptase inhibitors. Liver
function and immunovirological parameters were monitored throughout the study. Serial blood samples were drawn
to explore RAL pharmacokinetics. Plasma concentrations of protein unbound, total RAL, and RAL glucuronide were
determined by liquid chromatographytandem mass spectrometry.
Results. Ten patients with ESLD were analyzed in substudy 1. Despite an increased RAL exposure, RAL was well
tolerated in all patients and no patient had to stop RAL therapy because of adverse events. Four patients were analyzed in substudy 2. No pharmacokinetic interaction was observed between cyclosporine, mycophenolic acid, and
RAL. RAL tolerability was excellent; there were no episodes of acute rejection or opportunistic infection. HIV-RNA
levels remained controlled and CD4 cell counts remained stable in all patients throughout the study.
Conclusions. The results of the substudy 1 support RAL administration to patients with ESLD. Substudy 2 assesses the safety, tolerability, and efcacy of RAL therapy in HIV-infected patients after liver transplant. RAL might
be recommended as a suitable antiretroviral therapy in HIV-infected patients undergoing liver transplant.
Keywords.

end-stage liver disease; HIV; liver transplant; pharmacokinetics; raltegravir.

Raltegravir (RAL) was the rst human immunodeciency virus type 1 (HIV-1) integrase inhibitor to be
approved. It is orally administered at a dose of 400 mg

Received 9 April 2014; accepted 26 June 2014.

a
Members of the ANRS 148 Study Group are listed in the Appendix.
Correspondence: Caroline Barau, PharmD, PhD, Service de Pharmacie Clinique et
Pharmacocintique, Hpital Bictre, 78 avenue du Gnral Leclerc, 94275 Le Kremlin
Bictre, France ([email protected]).
Clinical Infectious Diseases
The Author 2014. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/ciu515

twice daily, in combination with other antiretroviral

agents. RAL is highly effective and well tolerated,
with a favorable safety prole and low potential for
drugdrug interactions [14]. The pharmacokinetic
properties of RAL have been characterized [5]. It is rapidly absorbed, with maximum plasma concentration
(Cmax) reached in a median time (Tmax) of about 3
hours in fasting conditions [6]. About 83% of the
RAL is bound to plasma proteins, mostly albumin [7],
and this drug is metabolized by the UDP-glucuronosyltransferase 1A1 (UGT1A1) isoenzyme [5, 8]. It is commonly thought that glucuronidation remains unaltered

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PATIENTS AND METHODS

Study Design and Population

The protocol of the multicenter end-stage LIVER disease and

RALtegravir-Agence Nationale de Recherche sur le Sida et
les hpatites (LIVERAL-ANRS) 148 study (EudraCT: 2009014616-36) was reviewed and approved by an institutional
review board (CPP-IDFVII, 2009) and competent health
authorities. All patients gave written informed consent before
participating in the study. For all patients, adverse events were
graded according to the ANRS toxicity grading scale for adverse
events in adults [14].
Patients were eligible in substudy 1 if they had ESLD (dened
as a Model for End-Stage Liver Disease [MELD] score of 15
and/or current or previous history of refractory ascites and/or
current or previous history of repeated digestive hemorrhage
and/or current or previous history of hepatic encephalopathy);
had a plasma HIV RNA load (VL) on antiretroviral therapy
<50 copies/mL for at least 6 months (Cobas TaqMan, Roche;

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limit of quantication 20 copies/mL); and had an HIV strain

fully sensitive to at least 2 antiretroviral drugs according to cumulative genotypes carried out on viral RNA together with
treatment history and no mutations related to RAL resistance
on HIV DNA sequencing at enrollment.
Patients included in substudy 1 were switched to a combined
antiretroviral treatment with 400 mg RAL twice daily and a
once-daily xed dose of tenofovir/emtricitabine or abacavir/
lamivudine. Safety and tolerability were assessed by follow-up
medical visits and laboratory measurements at screening
(4 weeks before RAL introduction), day 0 (RAL introduction),
and month 1 (M1), month 2 (M2), and month 3 (M3). Antiretroviral efcacy was assessed by determining VL and CD4 cell
counts at screening, M1, and M3. Liver function, as assessed by
the determination of MELD score, was monitored at screening
and until M3 after RAL introduction. Blood samples were collected 1 month after RAL introduction before morning drug intake and 1, 2, 3, 5, 7, and 9 hours after intake to assess RAL
pharmacokinetic parameters at steady state. Patients were
asked to remain in a fasting state for 1 hour after RAL intake.
Liver transplant recipients for viral cirrhosis related to hepatitis C or B or another cause of cirrhosis were included in substudy 2. The criteria for being registered on the French
transplant list include decompensated cirrhosis with liver failure (ascites, prothrombin time <50%, or international normalized ratio >1.5), elevated serum conjugated bilirubin >50 mol/L,
hypoalbuminemia <30 g/L, and symptomatic portal hypertension (gastrointestinal bleeding).
Immunosuppressive treatment, including cyclosporine or tacrolimus, corticosteroids, and mycophenolate mofetil hydrolyzed to mycophenolic acid (MPA), the active moiety, was
initiated in patients included in substudy 2 the next day following LT. Doses were adapted according to the blood concentrations of cyclosporine (target: 100400 ng/mL) and tacrolimus
(target: 515 ng/mL) or plasma Area Under the Concentrations
versus time curve during a 12-hour interval (AUC012) for MPA
(target: 3060 mg h/L) [15, 16]. All antiretroviral drugs were
discontinued on the day of transplant, and a RAL-based regimen associated with a combination of tenofovir/emtricitabine
or abacavir/lamivudine was initiated as soon as the results of
liver function tests normalized. Safety and tolerability were assessed at day 7 (D7; before RAL introduction), M1 (after RAL
introduction), and M2 and M3 posttransplant. VL was measured on D7, M1, and M3. For analyses of RAL pharmacokinetic parameters, blood samples were collected as described for
substudy 1, before (D7) and after (M1) RAL introduction,
respectively.
Drug Assays

Concentrations of calcineurin inhibitors were determined

by an immunoenzymatic chemiluminescent microparticle

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in liver dysfunction. Some investigations have shown that, indeed, this is dependent on the isoenzymes involved.
Although UGT1A9, UGT1A1, or UGT2B10 levels appear to
be maintained during liver dysfunction, recent investigations
evidenced a signicant decrease in UGT1A6 [9, 10]. As endstage liver disease (ESLD) is becoming an increasingly severe
problem in HIV-infected patients, with a rise in the demand
for liver transplant (LT), studies of the relevance of RALbased therapy in a context of severe liver disease are crucial. Despite recent advances in the treatment of chronic hepatitis B and
hepatitis C, LT remains the ultimate option for the treatment of
patients with decompensated liver cirrhosis and can now be
performed successfully in eligible HIV-infected patients [11].
In the period immediately following transplant, the immunosuppressive regimen generally includes calcineurin inhibitors,
cyclosporine or tacrolimus, mycophenolic acid, and corticosteroids. One major problem is the occurrence of pharmacokinetic
interactions between calcineurin inhibitors and many antiretroviral drugs that share the same metabolic pathway through cytochrome P450 3A4 (CYP3A4) [12]. Indeed, protease inhibitors
are potent CYP3A4 inhibitors [12], whereas nonnucleoside reverse transcriptase inhibitors are CYP3A4 inducers [13]. RAL is
not a CYP3A4 substrate; therefore, using an RAL-based regimen after LT may improve the management of the immunosuppressive treatment after antiretroviral introduction in the
posttransplant period.
The aims of this study were to evaluate the safety, efcacy,
and pharmacokinetic parameters of RAL in HIV-infected patients with ESLD and to assess the degree of pharmacokinetic
interaction between RAL and the immunosuppressive regimen
introduced after LT.

immunoassay method in the same laboratory (Architect, Abbott). MPA and RAL assays were performed in a centralized
laboratory. Plasma concentrations of total and unbound MPA
were determined by validated reverse-phase high-performance
liquid chromatography methods, after protein precipitation and
centrifugation through Centrifree devices (Millipore), respectively [17]. Limits of quantication were 0.1 and 0.025 mg/L, respectively. Plasma concentrations of total RAL, unbound RAL
and inactive RAL glucuronide were measured by liquid chromatographytandem mass spectrometry (LC-MS/MS). Total RAL
concentrations were determined after protein precipitation [18].
As we had no access to puried RAL glucuronide, this metabolite was hydrolyzed using -glucuronidase (Helix pomatia,
Sigma) during a 16-hour incubation at 37C [19] to yield
RAL, which was measured as described above. RAL glucuronide
concentrations were calculated as the difference between RAL
concentrations before and after hydrolysis. Unbound RAL was
assayed in ultraltrate by a separate validated LC-MS/MS method [7]. The limits of quantication were 2.5 and 1.0 ng/mL for
total and unbound RAL, respectively. For each of the methods
described here, within-day and between-day coefcients of

variation were <15%, as ascertained by internal quality controls

implemented throughout the study. Our laboratory participates
in a program of external quality control for total RAL and total
MPA assays.
Pharmacokinetic Data and Statistical Analysis

Table 1. Demographic Characteristics and Blood Parameters of Patients

Substudy 1 (n = 10)
Demographic Parameters
Age, y
BMI, kg/m
Weight, kg

M3 (n = 7)a

Screening (n = 10)

Sex, female/male, No.

Substudy 2 (n = 5)
D7 (n = 5)

M3 (n = 4)

3/7

0/4

50 (3963)

47 (4452)

21 (1628)
60 (4774)

22 (1830)
60 (4985)

23 (1624)
66 (5076)

19 (1622)
60 (4970)

Blood parameters
HIV/HCV coinfection
Lymphocytes, cells/L

763 (5301640)

8/10
907 (5201100)

365 (350380)

3/4
380 (330410)

CD4 count, cells/L

259 (57604)

260 (120315)

130 (109160)

76 (70100)

CD4 %
MELD score

25 (1443)
12 (526)

27 (2445)
8 (318)

38 (1042)
...

22 (1125)
...

Child-Pugh score

10 (614)

Serum creatinine, mol/L

Serum albumin, g/L

65 (3694)
28 (2242)

...

...

68 (4577)
...

...

89 (52117)
28 (2535)

132 (129138)
...

AST, IU/L

74 (25150)

89 (38120)

37 (22104)

66 (22105)

ALT, IU/L
GGT, IU/L

43 (6104)
70 (29261)

51 (43121)
68 (34191)

80 (9204)
303 (101423)

66 (3598)
148 (323628)

ALP, IU/L

126 (56273)

109 (52173)

230 (49413)

131 (652125)

35 (14397)
56 (3278)

19 (1232)
61 (3080)

51 (18116)
70 (63100)

33 (1053)
90 (73100)

Total bilirubin, mol/L

Prothrombin time, %
Factor V, %
INR

52 (33117)

59 (33139)

1.55 (1.202.59)

1.40 (1.172.71)

104 (83138)

125 (66150)

1.24 (0.971.40)

1.07 (0.851.21)

Values are expressed as median (range). Substudy 1: patients with end-stage liver disease; substudy 2: recipients of liver transplant.
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GGT, -glutamyltransferase;
HCV, hepatitis C virus; HIV, human immunodeficiency virus; INR, international normalized ratio; M1, month 1; M3, month 3; MELD, Model for End-Stage Liver Disease.
a

Two patients were transplanted before the M3 visit, and 1 patient did not take his visit at M3 but rather at M6.

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Pharmacokinetic parameters were calculated by a noncompartmental method, with Phoenix WinNonlin 1.3 (PharsightCertara). AUC values were calculated with the linear up/
log-down trapezoidal rule. In substudy 1, we calculated RAL
Area Under the Concentrations versus time curve during a
9-hour interval (AUC09) (up to last sample time) rather than
AUC012, due to the erratic nature of the pharmacokinetic proles obtained for RAL. In substudy 2, the absence of enterohepatic MPA recycling made it possible to calculate the AUC012
for MPA. The Cmax, Tmax, and predose trough concentrations
(Cmin) obtained were observed values. The unbound fraction
of RAL was determined as the AUC09 ratio of unbound RAL
to that of total RAL, and the unbound fraction of MPA was calculated as the AUC012 ratio of unbound MPA to total MPA.
Metabolic index was calculated from the AUC09 ratio of RAL

glucuronide to total RAL. Results are expressed as the median

(range). All statistical analyses were performed with GraphPad
Instat 3.05 (GraphPad Software, San Diego, California).
RESULTS

sequences analyzed included resistance-associated mutations

(RAMs): 1 each displayed the 41L, 67N, 69D, M184V, and
215Y mutations; 3 displayed the M184V or I RAM; and 1 displayed the 69T/S RAM. None of the 6 integrase gene sequences
analyzed presented any RAM likely to confer resistance to RAL.
Pharmacokinetic Parameters of RAL

Characteristics of the Study Population

The median pharmacokinetic parameters for RAL are summarized in Table 2 and are in the same range for both substudies.
The concentration of unbound RAL varied considerably between individuals in both populations (Figure 1). Whatever
the substudy, the unbound fraction of RAL was stable over
the dosing interval and was not correlated with albumin
concentration.
In patients with ESLD, median RAL AUC seemed to be unchanged whether measured in the presence or absence of ascites
(33 451 [range, 516354 830] ng h/mL, n = 8 or 13 247 and
65 972 ng h/mL, n = 2). Plasma concentrationtime proles
for total RAL and RAL glucuronide were similar (Figure 1).
In LT recipients, RAL glucuronide concentrations were slightly
higher than total RAL concentrations (Figure 2). The 3 patients
who received RAL concomitantly with a proton pump inhibitor
had the highest AUC09 values for total RAL (65 972, 42 189,
and 52 653 ng.h/mL).
Pharmacokinetic Parameters of Mycophenolic Acid
and Cyclosporine

All patients in substudy 2 received immunosuppressant therapy

including cyclosporine, MPA, and corticosteroids. The median

Table 2. Pharmacokinetic Parameters of Total and Unbound Raltegravir and Raltegravir Glucuronide in Substudy 1 and Substudy 2
Pharmacokinetic Parameters

Substudy 1 (n = 10)

Interpatient CV, %

Substudy 2 (n = 4)

Interpatient CV, %

421 (368148)
8759 (88916 203)

65
82

460 (1671927)
6953 (545414 812)

106
51

Total raltegravir
Cmin, ng/mL
Cmax, ng/mL
Tmax, h

2.0 (1.07.0)

AUC09, ng h/mL
Unbound raltegravir

33 451 (516365 972)

62
95

2.5 (1.04.9)
32 373 (16 23052 653)

61
51

Cmin, ng/mL

81 (111314)

83

82 (29295)

99

Cmax, ng/mL
Tmax, h

1574 (1762638)
2.0 (1.07.0)

88
62

866 (8312576)
2.5 (1.04.9)

67
61

AUC09, ng h/mL

6110 (9039863)

91

4190 (25336737)

42

Unbound fraction, %
Raltegravir glucuronide

18.6 (12.332.3)

17

13.9 (11.815.6)

13

Cmin, ng/mL

720 (8218 440)

112

4341 (5068322)

73

Cmax, ng/mL
Tmax, h

5072 (60625 378)

3.0 (2.07.2)

71
47

11 088 (542417 567)

5.1 (2.09.3)

55
56

20 801 (4483163 907)

75

48 762 (35 515113 696)

AUC09, ng h/mL
Metabolic ratio

0.9 (0.32.5)

71

2.1 (0.93.1)

57
49

Values are expressed as median (range).

Abbreviations: AUC0-9, area under the concentrationtime curve during a 9-hour time interval; Cmax, concentration of the peak; Cmin, predose concentration; CV,
coefficient of variation; Tmax, time to reach concentration peak.

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The main demographic characteristics and laboratory parameters are shown in Table 1. Ten patients were analyzed in substudy 1. The causes of ESLD were hepatitis C cirrhosis (8/10),
hepatitis B cirrhosis (1/10) and nodular regenerative hyperplasia (1/10). Eight of the 10 patients had a history of ascites before
their inclusion, and only 1 patient exhibited reoccurrence of
ascites after improvement. Median follow-up was 11 weeks
(range, 414 weeks).
Five LT recipients were included in substudy 2, of whom 2
also consented to participate in substudy 1. Four were analyzed.
The indications for LT were hepatitis B cirrhosis (1/5) and hepatitis C cirrhosis (4/5). Daily doses of cyclosporine and MPA
ranged from 175 to 550 mg twice daily and from 500 to 1000
mg twice daily, respectively. No modications of cyclosporine
or MPA dosage were made between D7 and M1. In this substudy, median follow-up was 12 weeks (range, 114 weeks).
One patient in substudy 1 and 2 patients in substudy 2 received RAL concomitantly with a proton pump inhibitor.
None of the other concomitant medication taken in either substudy was expected to have a clinically meaningful effect on
RAL metabolism. Five of the 13 viral transcriptase gene

Table 3. Pharmacokinetic Parameters of Cyclosporine and

Mycophenolic Acid in Substudy 2, at Day 7 and Month 1 After
Transplant

Pharmacokinetic Parameters

Day 7 After
Transplant

M1 After
Transplant

Total MPA
AUC012 normalized, mg h/L

17.8 (12.154.6)

13.5 (8.730.8)

0.73 (0.493.98)
4.6 (3.37.3)

0.69 (0.591.24)
5.0 (4.06.8)

15.5 (10.625.5)

14.6 (12.335.7)

Unbound MPA
AUC012 normalized, mg h/L
Unbound fraction, %
Cyclosporine
AUC012 normalized,
ng h/mL/mg

Figure 1. Plasma concentrations of total raltegravir (circles), unbound

raltegravir (triangles), and raltegravir glucuronide (squares) in the 10 patients with end-stage liver disease enrolled in substudy 1, one month
after raltegravir introduction.

Abbreviations: AUC0-12, area under the concentrationtime curve during a

12-hour time interval; M1, month 1; MPA, mycophenolic acid.

participate in the pharmacokinetic sampling. Viral replication

was <50 copies/mL throughout the study, and the median percentages of CD4 cells were 38% (range, 10%42%) at D7 posttransplant and 22% (range, 11%25%) at M3 of follow-up.

Safety and Tolerability

In substudy 1, VL remained <50 copies/mL and median CD4

cell count was 259 cells/L (range, 57604 cells/L) and 260
cells/L (range, 120315 cells/L) at screening and M3, respectively. Median MELD score was 12 (range, 526) at screening
and 8 (range, 318) at M3.
In substudy 2, after a median follow-up of 3 months, 4 of the
5 patients were still alive, with good graft function and no acute
rejection or opportunistic infection. One patient died immediately after LT, due to bacterial sepsis without being able to

Figure 2. Plasma concentrations of total raltegravir (circles), unbound

raltegravir (triangles), and raltegravir glucuronide (squares) in the 4 surviving liver transplant patients enrolled in substudy 2, one month after raltegravir introduction.

DISCUSSION
In this study, we determined the pharmacokinetic parameters
of RAL in patients with ESLD and in LT recipients. This information is important because the target population for RAL
treatment includes HIV/hepatitis C virus (HCV)coinfected
patients with hepatic impairment. Our ndings suggest that despite an increased RAL exposure in patients with ESLD, RAL
was well tolerated. Our study therefore supports the administration of RAL to patients with ESLD. This study also demonstrated the absence of pharmacokinetic interaction between RAL
and cyclosporine and MPA after LT. RAL may therefore be considered a suitable antiretroviral treatment for HIV-infected patients undergoing LT.
RAL Cmin, Cmax, and AUC reported in substudy 1 in patients
with ESLD (Cmin range, 368148 ng/mL) were higher than those
observed in patients with normal liver function (Cmin range, 15
2223 ng/mL) [20]. We conrmed the high variability of RAL parameters, showed by the high interpatient coefcient of variation.
This result is in line with previous ndings [21]. Many factors
potentially impacting the variability of RAL pharmacokinetics
have been identied, such as food intake and the coadministration of proton pump inhibitors [6, 22] accounting for the
high intersubject variability. In our study, RAL pharmacokinetic
parameters were measured in the fasting state, which may account for the higher concentrations reported in subjects with
normal liver function and no food restriction [20, 23]. We obtained higher RAL Cmax and AUC values than those reported

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pharmacokinetic parameters for cyclosporine and MPA are

summarized in Table 3 and are in the same range between
D7 and M1 posttransplant.

Values are expressed as median (range).

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In transplant recipients, the range of the RAL metabolic

index was close to that reported in patients with normal liver
function included in the ANRS 139 TRIO study (0.93.1 vs
0.43.3; C. Barau, personal unpublished work), indicating that
the liver grafts had metabolizing capacity. No interaction was
observed between cyclosporine, MPA, and RAL. Exposure to
cyclosporine and MPA was not modied by the introduction
of RAL, as expected, given the different metabolic pathways of
these molecules. Virological efcacy was maintained in patients
switching from a ritonavir-boosted protease inhibitor regimen
to a regimen based on RAL associated with 2 nucleoside reverse
transcriptase inhibitors, despite the low genetic barrier of
resistance of RAL. We observed 1 case of diabetes mellitus
among the LT recipients, induced by the combination of steroids and immunosuppressive agents. The small decrease in
CD4 cell counts observed following LT could be related to
immunosuppression. One patient, who exhibited leukopenia
probably due to MPA treatment, died immediately after LT
from bacterial sepsis. Cytolysis, cholestasis, and an increase in
bilirubin events after LT were related to the recurrence of
HCV infection on the graft, which represents the main severe
complication after LT for HIV/HCV-coinfected patients. The
absence of clinically relevant drugdrug interactions and the
good tolerance makes RAL a very attractive candidate for HIV
treatment in patients undergoing LT, conrming the ndings of
Tricot et al [31].
This study was subject to several limitations. First, although
RAL pharmacokinetic parameters were not directly compared
between the patients and healthy controls, we can compare
pharmacokinetic parameters in ESLD with those observed in
LT patients who have a prompt graft recovery. Second, following
the initiation of this study, Iwamoto et al [22] reported that proton pump inhibitors induced a 3- to 4-fold increase in RAL
AUC and Cmax in healthy subjects. However, in HIV-infected
patients, the increase in RAL concentrations was lower than
what was observed in healthy subjects, probably because these
patients often have achlorhydria or hypochlorhydria [6]. In this
study, although high AUC09 values for total RAL were noticed
in the 3 patients taking proton pump inhibitors, the safety prole of RAL was similar overall to that of patients not using such
drugs. Third, this study was conducted in a small number of patients, but our safety and pharmacokinetic data nevertheless
support the use of RAL in patients with liver disease before
and after LT. Finally, our strategy is applicable only to patients
undergoing very close monitoring that will detect early virological failure and prompt a switch to a rescue antiretroviral regimen as needed.
In conclusion, despite high exposure, RAL was well tolerated
by patients with ESLD. Our study supports the administration
of RAL to patients with ESLD at the approved dosing. Our results also assess the safety, tolerability, and efcacy of RAL

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by Iwamoto et al [24] for patients with moderate hepatic insufciency, but our results are consistent with those recently published by Hernandez-Novoa et al [25], who demonstrated
higher levels of RAL exposure in patients with advanced cirrhosis,
with no increase in toxicity, in 10 HIV/HCV-coinfected patients.
An increase in the unbound fraction of drugs that normally
bind strongly to albumin has been reported in patients with severe liver disease [26]. In our study, the unbound fraction of
RAL was 18.6% (range, 12.3%32.3%), consistent with the
mean unbound fraction of 17% previously reported for patients
with normal liver function [5]. The change in unbound RAL
concentration over time seems to parallel that of total RAL concentration, indicating a lack of change in protein binding over
the dosing interval. No correlation with albumin concentration
was observed, in contrast to previous ndings [7], probably because all the patients presented hypoalbuminemia, with albumin concentrations <35.0 g/L and falling within a narrow
range (23.735.0 g/L). We analyzed, for the rst time, the pharmacokinetic parameters of RAL glucuronide and RAL metabolic index. The change in RAL glucuronide concentration
in plasma over time closely paralleled that of total RAL concentration, with the highest RAL glucuronide concentration measured 3.0 hours (range, 2.07.2 hours) after drug intake. The
median metabolic index in patients with ESLD was lower
than that measured in 9 HIV-infected patients with normal
liver function included in the ANRS 139 TRIO study (0.9
[range, 0.32.5] vs 1.2 [range, 0.43.3]; C. Barau, personal unpublished work), suggesting weak and not clinically signicant
impairment of liver metabolism of RAL in patients with ESLD.
Indeed, unlike cytochrome-based metabolism, the glucuronidation of various drugs has been shown to be unaffected by severe
liver disease [9, 27, 28]. The underlying mechanism has not been
completely elucidated, but may involve extrahepatic metabolism, particularly in the kidney, or the release or activation of
latent enzymes during liver injury [28, 29]. It was demonstrated
that liver diseases have no signicant effect on UGT1A1 protein
levels [10], conrming the little potential for altered glucuronidation of RAL observed in vivo in this study.
RAL was previously demonstrated to be a safe option for
HIV/HCV-coinfected patients with brosis stage 2 or cirrhosis [30]. Our study conrms these results, because despite the
high RAL concentrations observed in the patients with ELSD,
RAL was well tolerated with no aggravation or are-up of alanine aminotransferase/aspartate aminotransferase activity and
no VL breakthrough. Bilirubin concentration and MELD
score decreased in 4 patients who switched from atazanavir, a
UGT1A1 inhibitor, to RAL. MELD score remained stable
throughout the study, and no clinical events were observed.
No adjustment of the dose of RAL was required in this population, and no risk of subtherapeutic concentrations is to be expected in case of ascites.

therapy in HIV-infected patients after LT. Moreover, cyclosporine and MPA exposure remained unchanged after the introduction of RAL, avoiding the need to manage drugdrug
interactions during the immediate post-LT period. RAL might
be recommended as a suitable antiretroviral therapy in HIVinfected patients undergoing LT.
Notes
Acknowledgments. We express our gratitude to all the patients who
participated in this study.
Financial support. This trial was conducted with the support of Merck
Sharp & Dohme-Chibret.
Potential conicts of interest. All authors: No reported conicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the content of the manuscript have been disclosed.

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APPENDIX
The members of LIVERAL-ANRS 148 Study Team were
as follows: Chair, E. Teicher; Co-chair, J.-C. Duclos-Valle;
Methodology, J.-P. Aboulker; Project managers, J. Braun and

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I. Fournier; Statistician, C. Vincent; Monitoring and data management, A. Arulananthan, V. Eliette, F. Euphrasie, B. Guillon,
P. Ralaimazava; Virologists, S. Ham-Boukobza, A.-M. RoqueAfonso; Pharmaceutical, L. Bonhomme-Faivre, E. Rudant;
Pharmacologist, A.-M. Taburet. Scientic Committee: J. P.
Aboulker, L. Bonhomme-Faivre, J. Braun, S. Coufn-Cadiergues,
C. Delaugerre, J.-C. Duclos-Valle, F. Durand, S. Ham-Boukobza,
P. Ralaimazava, A.-M. Taburet, E. Teicher, C. Vincent, D. Vittecoq.
Data Safety and Monitoring Board: P. Flandre, R. Garraffo,

J. Ghosn, A. Marraud and G. Pageaux. Participating Centers and

Investigators (all in France): Hopital de Bictre (Le Kremlin Bictre): E. Teicher, O. Derradji, D. Vittecoq, C. Bolliot,
F. Churaqui; Hopital Paul Brousse (Villejuif ): E. Teicher,
T. M. Antonini, A. Coilly, J.-C. Duclos-Valle, P. Ichai, O. Ogier,
M. Belnard; Hopital Saint-Louis (Paris): J.-M. Molina, V. De
Lastours, S. Gazaignes, D. Ponscarme, H. Sauvageon; Hopital
de la Croix-Rousse (Lyon): P. Miailhes, J. Kof, S. Radenne,
C. Brochier.

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