Enfuvirtide: A Safe and Effective Antiretroviral Agent for Human Immunodeficiency Virus Infected Patients Shortly After Liver Transplantation

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1 LIVER TRANSPLANTATION 15: , 2009 ORIGINAL ARTICLE Enfuvirtide: A Safe and Effective Antiretroviral Agent for Human Immunodeficiency Virus Infected Patients Shortly After Liver Transplantation Elina Teicher, 1,5,6 Chadi Abbara, 2 Jean-Charles Duclos-Vallée, 3,5,6 Teresa Antonini, 3 Laurence Bonhomme-Faivre, 2 Delphine Desbois, 4 Didier Samuel, 3,5,6 and Daniel Vittecoq 1 1 Département Médecine Interne et Infectiologie, 2 Département Pharmacie, 3 Centre Hépato-Biliaire, and 4 Laboratoire de Microbiologie, AP HP Hôpital Paul Brousse, Villejuif, France; 5 INSERM, Unité 785, Villejuif, France; and 6 Univ Paris-Sud, UMR-5 785, Villejuif, France The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV) coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm 3. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence. Liver Transpl 15: , AASLD. Received October 27, 2008; accepted April 19, The treatment of human immunodeficiency virus (HIV) infection has evolved rapidly, and the introduction of highly active antiretroviral (ARV) therapy has significantly decreased mortality and morbidity. HIV infection is now managed as a chronic disease and is no longer a contraindication for liver transplantation (LT), provided that HIV replication is under control. 1,2 Several reports have clearly demonstrated that LT is feasible in HIVinfected patients. 3-6 Current guidelines concerning the treatment of HIVinfected patients prefer the use of a protease inhibitor (PI) boosted with ritonavir or a non-nucleoside reverse transcriptase inhibitor backbone combined with 2 nucleoside reverse transcriptase inhibitors (NRTIs) in or- Abbreviations: ABC, abacavir; ALT, alanine aminotransferase; ARV, antiretroviral; AST, aspartate aminotransferase; CsA, cyclosporine A; ENF, enfuvirtide; FK, tacrolimus; FTC, emtricitabine; GGT, gamma glutamyl transferase; HBV, hepatitis B virus; HCV, hepatitis C virus; HDL, high-density lipoprotein; HIV, human immunodeficiency virus; IS, immunosuppressant; LAM, lamivudine; LDL, low-density lipoprotein; LPV, lopinavir; LPV/r, lopinavir/ritonavir; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; N/D, not determined; NRTI, nucleoside reverse transcriptase inhibitor; P1, period 1; P2, period 2; P3, period 3; PI, protease inhibitor; T20, enfuvirtide; TDF, tenofovir; TGL, triglyceride. Address reprint requests to Elina Teicher, Département de Médecine Interne et d Infectiologie, Hôpital Paul Brousse, Avenue Paul Vaillant Couturier, Villejuif, France. Telephone: ; FAX: ; elina.teicher@pbr.aphp.fr DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 ENFUVIRTIDE: SAFE AND EFFECTIVE 1337 der to maintain plasma HIV RNA levels below the threshold of detection. 7 Recommendations by the Centers for Disease Control and Prevention also accept an alternative unboosted PI regimen (including atazanavir or fosamprenavir). 8 However, their use should be considered only under specific circumstances. 7 Liver toxicity is a known side effect of non-nucleoside reverse transcriptase inhibitors 9,10 and is more frequently associated with nevirapine (12%) than with efavirenz (4%). 11,12 In our experience, a PI in combination with 2 NRTIs is a more widely used regimen in liver graft patients; we prefer not to use non-nucleoside reverse transcriptase inhibitors for safety reasons. Indeed, among a total of 88 coinfected transplant patients treated in our center, 65 received a PI-containing regimen, which was mainly lopinavir/ritonavir (LPV/r; communication accepted for CROI 2009). LPV/r, in combination with an NRTI, exhibits sustained antiviral activity in both ARV-naïve and PI-experienced HIV-1 infected patients. 13,14 The clinical use of LPV/r as a component of ARV regimens has been shown to be associated with an incidence of hepatotoxicity ranging from 1% to 9.5% during clinical trials. 15 In addition, solid organ transplantation in HIV-infected individuals requires the concomitant use of immunosuppressant (IS) and ARV agents. IS agents such as cyclosporine A (CsA) and tacrolimus (FK) play a key role in preventing rejection in transplant patients. In fact, both IS and PI are substrates and inhibitors of the cytochrome P450 metabolizing enzyme CYP3A4 and increase plasma concentrations of CYP3A4 substrates. Moreover, IS agents are also substrates and inhibitors of P-glycoprotein, a transporter found on the apical membranes of intestinal epithelial and hepatic cells and responsible for reducing the absorption and increasing the excretion of its substrates. 16 In intestinal cells, P-glycoprotein and CYP3A4 act together to inhibit intestinal drug absorption and increase intestinal drug metabolism. 17,18 Thus, the concomitant administration of inhibitors containing substrates of both P-glycoprotein and CYP3A4, such as IS agents with PIs, would therefore be expected to increase the uptake and systemic blood concentrations of IS, prolonging the elimination halflife. 19 Consequently, a major decrease in CsA and FK dose regimens is necessary to prevent toxicity, and this requires the collection of numerous blood samples to verify trough concentrations and their stability. Jain et al., 20 our team, 21 and several trials have determined that patients treated with a PI-based regimen require only 0.5 to 1 mg of FK per week and low daily doses of CsA to maintain trough concentrations within the therapeutic range Thus, if a PI is administered in combination with FK or CsA, very careful management is necessary to maintain IS concentrations at a therapeutic level that will prevent graft rejection while also preventing life-threatening side effects because of the narrow therapeutic margin of these drugs. 25,26 For these reasons, this study was focused on achieving effective anti-hiv therapy that could avoid such drug interactions, and it was decided to test the use of a fusion inhibitor. Enfuvirtide (ENF) is a 36 amino acid synthetic peptide that inhibits the fusion of HIV-1 with CD4 cells. This drug, in combination with an optimized background regimen, has been tested in populations of patients with very advanced HIV infection exhibiting resistance to various anti-hiv treatments and clearly enables significant and sustained viral suppression and immunological benefits. 27,28 ENF is broken down into smaller peptides and free amino acids by peptidases/proteinases, principally in the liver and kidneys. Like most drugs with a peptide structure, ENF appears to have a low potential for metabolic drug-drug interactions and a consistent safety record in terms of liver toxicity. 29,30 ENF has been shown to have only mild effects on cytochrome P450 isoenzymes. Preclinical studies showed that repeated subcutaneous injections of ENF in rats did not induce hepatic metabolism, as assessed by the monitoring of increases in liver weight or the content or activities of CYP1A2, CYP2B1/2, or CYP3A1/2. 30 Metabolic interactions with ENF therefore seem unlikely. However, no formal studies concerning the concomitant administration of ENF with IS agents have been performed in patients with liver impairment or following LT. It was thus decided to assess the impact of ENF on the management of IS agents and the follow-up of LT recipients coinfected with hepatitis C virus (HCV), hepatitis B virus (HBV), and HIV through a comparison of an ENF-based regimen with an LPV/r-based ARV regimen. PATIENTS AND METHODS This was an observational study of LT recipients with HIV coinfection treated with ENF or LPV/r in combination with 2 NRTI drugs. The primary objective was to compare the management of IS agents administered with either ENF or LPV/r. The secondary objective was to assess the efficacy and safety of both ARV regimens in this patient population. The study was designed to last for 3 months following LT. Up to December 2005, grafted patients received ENF in combination with 2 nucleosides. We decided to compare these patients with LPV/r-exposed patients, matching them according to sex and age. This PI is frequently prescribed to transplant recipients in our hospital. To be eligible for LT, plasma HIV RNA levels had to be undetectable, that is, less than 50 copies/ml, this being the limit of detection of the ultrasensitive assay employed (COBAS AmpliPrep/COBAS TaqMan HIV-1 test, Roche). Other conditions included a stable ARV regimen, CD4 T-cell counts higher than 100/mm 3, and no history of opportunistic infections. ARV was discontinued during transplant surgery and the immediate postoperative period in order to ensure

3 1338 TEICHER ET AL. that IS concentrations remained predictable. ARV was reintroduced 14 days after LT, the time necessary to normalize liver function parameters and to achieve stable IS levels in the blood. The IS drug employed was FK or CsA, the dose being adjusted to maintain trough concentrations within the therapeutic range associated with prednisone. In all patients, corticosteroid therapy was initiated at a dose of 5 mg/kg/day and then reduced to 0.3 mg/ kg/day at the end of the first week; it was tapered to 10 to 15 mg/day during the first 3 months post-lt, and this was followed by gradual withdrawal over the next 3 months. All patients received 600 mg of cotrimoxazole and 10 mg/kg/day gancyclovir as primary prophylaxis plus 20 mg/day omeprazole and 0.6 ml/day heparin according to the standard protocol. The ARV regimen included NRTIs combined with LPV/r by mouth twice daily or ENF administrated subcutaneously twice daily at the recommended doses. Clinical examinations and liver biochemistry tests were performed daily during the first 3 weeks of the postoperative period, 3 times weekly over the next month, then once weekly for 3 months, and once monthly thereafter. Rejection events were graded according to the Banff scale. 31 Blood trough concentrations of FK or CsA were determined daily during the immediate postoperative period, at the introduction of the ARV drug, and at regular intervals thereafter as a function of the patient s clinical status once the steady state had been reached. IS dose schedules were adjusted to maintain FK trough concentrations between 8 and 20 ng/ml from day 0 to week 6 and between 5 and 15 ng/ml after week 6 and to maintain CsA trough concentrations between 310 and 450 ng/ml from day 0 to week 2 and between 175 and 350 ng/ml from week 2 to month 3. Blood samples were drawn in the morning before the scheduled administration of drugs and 12 hours after the last dose of FK or CsA. Blood was drawn into tubes containing ethylene diamine tetraacetic acid for the routine morning monitoring of CsA and FK concentrations. Whole-blood CsA trough concentrations were determined after protein precipitation with a fluorescence polarization immunoassay on an Axsym machine (Abbott Diagnostics, Rungis, France) with a cyclosporine II reagent kit. Wholeblood FK trough concentrations were determined after protein precipitation by the enzyme-multiplied immunotechnique on an IMx machine (Abbott Diagnostics) with an FK reagent kit. Trough concentrations of FK or CsA in the blood were evaluated during 3 periods. Period 1 extended from LT to the reintroduction of ARV therapy. Period 2 ran from the day on which ARV therapy was introduced to the end of the first month after LT and was followed by period 3, which ran from the end of the first month to the end of the third month post-lt. As a secondary endpoint, assessments were also made of the efficacy and safety of the ARV regimens by means of biochemical evaluations of liver parameters, plasma creatinine concentrations, lipid parameters, CD4 cell counts, and the HIV-1 plasma viral load. Statistical Analysis Doses and trough concentrations for each subject, as determined by routine therapeutic monitoring, were averaged for each ARV group and each period. Data are reported as the mean standard deviation or as the median and range (minimum to maximum). Statistical analysis was performed with R software (R Foundation for Statistical Computing, Vienna, Austria). RESULTS Eighteen HIV/HCV coinfected LT recipients and 4 HIV/HBV coinfected LT recipients were included in this study. Eleven patients were treated with the ENF regimen. These patients were matched for age and sex with the 11 patients receiving the LPV/r regimen. The length of exposure to ARV therapy prior to transplantation was 9.2 years (range: 2-15 years) for patients in the LPV/r group and 8.5 years (range: 2-15 years) for patients in the ENF group. The number of ARV drugs received prior to transplantation was 5 in both groups. The mutation profiles for HIV-1 found in ENF patients were as follows: 2 patients exhibited resistance mutations for AZT-D4T-3TC, and 1 of these also displayed mutations for saquinavir, nelfinavir, and indinavir. In the LPV/r group, 3 patients exhibited resistance mutations for AZT-D4T-3TC, and 2 of these patients also displayed mutations for nelfinavir, saquinavir, and indinavir. As for the NRTI combination, 10 patients in the ENF group received emtricitabine (FTC) and tenofovir (TDF), whereas the remaining patient in this group received a combination of lamivudine (LAM) and abacavir (ABC). In the LPV/r group, 5 patients received FTC and TDF combination therapy, 4 patients received ABC and TDF, and 2 patients received ABC and LAM. Fourteen patients received FK, and 8 patients received CsA, the doses being adjusted to maintain blood concentrations of these drugs within the therapeutic range, as described previously. The demographic, biological, and immunological characteristics of the patients are listed in Tables 1 and 2. Among patients treated with ENF in period 1 (P1; immediately after LT but before the reintroduction of ARV), the median CD4 cell count was 178 cells/mm 3 (range: ), and HIV RNA levels remained undetectable. Prothrombin, V factor, and albumin levels were normal, whereas total bilirubin levels were abnormally high at 57 mol/l with mild cytolysis. Creatinine clearance was normal. In the LPV/r group, the median CD4 cell count was 237 cells/mm 3 (range: ), HIV RNA levels remained undetectable, and bilirubin levels were high at 45 mol/l despite normal liver function. The kidneys were also found to be functioning normally. During period 2 (P2), median CD4 cell counts re-

4 ENFUVIRTIDE: SAFE AND EFFECTIVE 1339 TABLE 1. Demographic Characteristics of the HIV-Positive Transplant Recipients Characteristic Enfuvirtide Group (n 11) Lopinavir/Ritonavir Group (n 11) Age (years) 44 (33 53) 44.5 (39 58) Sex (%) Male 9 (81) 10 (90) Female 10 (19) 1 (10) Weight (kg) 68 (58 82) 63 (57 80) Confection (%) HBV 2 (19) 2 (19) HCV 9 (81) 9 (81) MELD score* 20 (15 30) 19 (10 37) ARV drugs before LT* 5 (3 8) 5 (3 7) Length of ARV regimen before LT (years)* 8.5 (2 15) 9.2 (2 15) Abbreviations: ARV, antiretroviral; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; LT, liver transplantation; MELD, Model for End-Stage Liver Disease. *Values are expressed as the median (range). TABLE 2. Clinical and Laboratory Features of the HIV-Positive Liver Transplant Recipients LPV (n 11) ENF (n 11) P1 P2 P3 P1 P2 P3 Prothrombin time 74 (44 84) 75 (60 100) 90 (78 100) 92 (60 100) 84 (74 100) 87 (73 100) V factor (%) 102 (65 138) 105 (72 140) 107 (78 140) 97 (69 150) 83 (70 90) 84 (75 90) Albumin (g/l) 31 (30 40) 33 (30 41) 33 (30 41) 35 (30 38) 35 (32 38) 36 (30 40) Bilirubin ( M) 45 (17 133) 12 (8 22) 15 (9 50) 57 (30 76) 40 (5 55) 23 (7 55) AST (IU/L) 55 (28 108) 54 (21 149) 44 (13 125) 64 (29 357) 80 (15 432) 105(15 400) GGT (IU/L) 250 (51 619) 238 (44 597) 267(18 317) 388 (76 644) 284 (24 951) 769(24 470) ALT (IU/L) 168 (54 520) 95(26 211) 91(11 195) 99 (23 293) 99 (10 330) 103(35 291) Creatinine clearance 94 (50 167) 95 (74 167) 91 (71 170) 89 (50 137) 109 (75 149) 103 (63 165) (ml/minute) HIV RNA (copies/ ml) CD4 (cells/ L)* 237 (50 715) 190 ( ) 240 (90 410) 178 (70 300) 187 (60 410) 208 (80 470) Cholesterol (mmol/ 3.3 (1 5.6) N/D 4.4 ( ) 3.4 (2.3 5) N/D 3.7 ( ) L) LDL (mmol/l) 1.9 ( ) N/D 2.4 ( ) 2.6 ( ) N/D 1.8 ( ) HDL (mmol/l) 0.8 ( ) N/D 0.9 ( ) 0.8 ( ) N/D 0.9 ( ) TGL (mmol/l) 1.3 ( ) N/D 2.3 ( ) 1.1 ( ) N/D 1.4 ( ) NOTE: Values are expressed as the median (range). Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ENF, enfuvirtide; GGT, gamma glutamyl transferase; HDL, high-density lipoprotein; HIV, human immunodeficiency virus; LDL, low-density lipoprotein; LPV, lopinavir; N/D, not determined; P1, period 1; P2, period 2; P3, period 3; TGL, triglyceride. * Before liver transplantation, the CD4 count was 262 cells/ L ( cells/ L) for patients in the LPV group and 309 cells/ L ( cells/ L) for patients in the ENF group. mained at about 200 cells/mm 3 in both groups, and HIV RNA remained undetectable. Kidney parameters were normal, and both groups displayed signs of mild cytolysis and cholestasis. During period 3 (P3), HIV RNA remained undetectable in both groups, and median CD4 cell counts remained at about 200 cells/mm 3. Creatinine clearance was normal with persistent mild anicteric cytolysis and cholestasis. During all 3 periods, both groups of patients exhibited normal values for lipid parameters (cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides). The trough concentrations and doses applied under the IS regimen (FK or CsA) over the 3 periods are summarized in Table 3. During P1, daily doses and trough concentrations of FK and CsA were similar in both groups. In P2, the reintroduction of LPV/r therapy with the FK or CsA regimen decreased the IS dose required to maintain trough concentrations within the therapeutic range to 0.3 mg/day for FK and 75 mg/day for CsA. By

5 1340 TEICHER ET AL. TABLE 3. FK and CsA Doses and Trough Concentrations When They Were Administered Alone (P1), When They Were Combined with Antiretroviral Treatment (P2), and After 3 Months of Follow-Up (P3) P1 P2 P3 Concentration (ng/ml) Dose (mg/day) Concentration (ng/ml) Dose (mg/day) Concentration (ng/ml) Dose (mg/day) CsA LPV ( ) ( ) (25 100) T ( ) ( ) ( ) FK LPV (1 14) ( ) ( ) T (1 20) (1 16) (1 15) NOTE: The target concentrations for FK in the blood were 8 to 20 ng/ml from day 0 to week 6 and 5 to 15 ng/ml after week 6. The target concentrations for CsA in the blood were 310 to 450 ng/ml from day 0 to week 2 and 175 to 350 ng/ml from week 2 to month 3. Concentrations are expressed as the mean standard deviation. Doses are expressed as the median (range). Abbreviations: CsA, cyclosporine A; FK, tacrolimus; LPV, lopinavir; P1, period 1; P2, period 2; P3, period 3; T20, enfuvirtide. contrast, IS doses were not modified by the reintroduction of ENF. Subjects receiving ENF required constant daily doses of IS, with no change to the mean trough IS concentrations being observed over the 3 periods. Nevertheless, significantly smaller CsA and FK dosage reductions were observed during P3 in both groups. Subjects receiving the LPV/r-containing regimen required a dramatic reduction in their CsA or FK doses as well as a longer interval between doses. ENF therapy was discontinued definitively in 1 patient 2 months after its introduction because of the local intolerance of subcutaneous injections and ARV therapy. This patient was switched to treatment with LPV/r. No rejection events or acquired immune deficiency syndrome related events were reported. An early recurrence of HCV was observed in 18 of the coinfected patients, but none were treated for this during 3 months following LT. No HBV replication was detected in the 4 coinfected patients included in this study. DISCUSSION Effective ARV therapy and the careful management of IS concentrations are crucial to the long-term success of LT in HIV-coinfected patients, particularly during the immediate posttransplant period. For this reason, we decided to perform a comparative analysis to assess the efficacy of IS management in HIV-positive patients treated with a combination of 2 NRTIs and either a PI or a fusion inhibitor (ENF). Shortly after LT, different pharmacological and clinical parameters were assessed during 3 periods. These included FK and CsA trough concentrations and doses, liver and kidney function parameters, and immunological and virological data. P1 corresponded to the immediate posttransplant period prior to the reintroduction of ARV therapy at a time when the patient s liver function was returning to normal. P2 corresponded to the reintroduction of ARV agents. This time point was considered crucial for assessing the impact of ARV therapy on IS pharmacokinetics. This reintroduction generally took place about 15 days after LT. 21 P3 extended from the end of the first month to the end of the third month post-lt. By this time, the patient s liver and kidney functions had returned to normal, with the HIV RNA viral load being controlled by effective ARV treatment. In addition, steady-state plasma concentrations of IS drugs were maintained within the therapeutic range. Patients on the ENF-based regimen required similar doses of FK or CsA during all 3 evaluation periods in order to maintain therapeutic plasma concentrations of IS. These doses were similar to those required by patients in the PI-based regimen group during the first period (before ARV reintroduction). No adjustment to the IS dose was required in patients on the ENF-based regimen between the immediate postoperative period and 2 months after LT. During P3, trough IS concentrations (FK and CsA) in both groups of patients were adjusted to the lowest effective level, the aim being to prevent any severe recurrence of HCV after LT in all HIV/HCV coinfected patients that could be potentialized by marked immunosuppression. The management of IS dosing was more complicated under the LPV/r regimen. It was also more difficult to achieve concentrations within the therapeutic range. In fact, lower IS doses were required, the interval between doses being adapted individually to take account of the high degree of interindividual variability regarding IS bioavailability and clearance. Thus, during the concomitant administration of PIs and IS, patients must be managed carefully in order to maintain FK or CsA concentrations at appropriate levels that will prevent graft rejection and any life-threatening adverse effects. In order to achieve similar trough levels, individuals on the LPV/r-based regimen required lower doses of IS and a longer dosing interval than patients receiving the ENF ARV regimen. In practice, the lowest dosage forms of FK and CsA contain 0.5 and 10 mg of active sub-

6 ENFUVIRTIDE: SAFE AND EFFECTIVE 1341 stance, respectively. Thus, for patients requiring the lowest doses, the intervals between doses were prolonged and adapted to the individual. Most patients on the LPV/r-based regimen needed to receive a dose of FK once every 1 to 2 weeks. Management was therefore difficult as patients often forgot their dose schedule. No discontinuations of ARV therapy due to liver toxicity or other severe adverse events were reported during the 3 study periods. Nevertheless, ENF therapy was withdrawn in 1 patient 2 months after its introduction because of a local intolerance of subcutaneous injections. This patient was subsequently switched to LPV/r, with an adjustment of the FK dosage to 0.5 mg every 2 weeks rather than the 9 mg per day taken while on treatment with ENF. The duration of this study was 3 months. At the end of the third period, no deaths had occurred among the 22 LT recipients coinfected with HIV who had been included in the study. None of the patients developed opportunistic infections. No significant changes in CD4 cell counts or HIV replication levels (which were controlled throughout the study period) were observed during the 3 periods. Both ARV regimens displayed high levels of virological efficacy. Both groups of patients displayed mild cytolysis and cholestasis after transplantation because of the rapid recurrence of HCV infection. HCV relapses occurred some hours after LT in all patients with a detectable HCV viral load prior to LT, their liver biopsy specimens revealing acute hepatitis. Some patients presented suppress with a recurrence of severe cholestatic hepatitis together with high gamma glutamyl transferase levels. None of the patients displayed any liver toxicity attributable to their ARV therapy. Other studies have shown that coinfection is an additional factor contributing to the likelihood of developing hepatotoxicity while a patient is on highly active ARV therapy, this factor being associated with 4.7 times as many liver function test abnormalities in patients taking LPV/r versus those observed in HCV-free subjects. 32 Chihrin et al. 33 showed that the duration of LPV/r treatment is a risk factor associated with a higher frequency of grade 3/4 alanine aminotransferase abnormalities (odds ratio: 3.18) in coinfected patients. The present study was designed to assess the feasibility of ENF treatment in a very complex population during a very critical period, shortly after transplantation. This unconventional regimen, involving the use of ENF with 2 NRTIs, is not endorsed by any guidelines. To our knowledge, this is the first and largest study ever carried out to assess an ENF-based regimen in HIV-infected transplant patients. Despite the limitations of this study, we observed a clear difference in the pharmacokinetic behavior of IS agents between subjects receiving the LPV/r and ENF regimens. The replacement of a PI-boosted regimen by an ENFbased regimen immediately after LT could shorten hospitalization and prove cost-effective. A smaller number of blood samples may be required to ensure that target concentrations are attained and to complete the standard follow-up of immunological and virological efficacy. However, the clinical benefits of ENF in this population must be weighed against the problems encountered by some patients regarding the administration of this drug because of local intolerance. Other new and effective ARV agents, such as integrase inhibitor (raltegravir), may also constitute an alternative to PI when combined with IS agents. Indeed, these ARV agents are not metabolized by cytochrome P450, so their use could be of interest in the case of severe hepatic disturbances that may occur during a later stage following LT. In conclusion, ENF is a safe and efficient alternative to standard ARV therapy, facilitating the management of drug-drug interactions during the immediate post-lt period. Finally, the low level of liver toxicity observed with ENF renders this drug an attractive option in cases of hepatic dysfunction in LT recipients and particularly in cases of severe, acute HCV recurrence. ACKNOWLEDGMENT The authors thank Anne-Marie Taburet, Celine Duval, and Claire Mony for their assistance. REFERENCES 1. Samuel D, Weber R, Stock P, Duclos-Vallee JC, Terrault N. Are HIV-infected patients candidates for liver transplantation? J Hepatol 2008;48: Stock PG, Roland ME, Carlson L, Freise CE, Roberts JP, Hirose R, et al. Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study. Transplantation 2003;76: Terrault NA, Carter JT, Carlson L, Roland ME, Stock PG. Outcome of patients with hepatitis B virus and human immunodeficiency virus infections referred for liver transplantation. Liver Transpl 2006;12: Duclos-Vallee JC, Feray C, Sebagh M, Teicher E, Roque- Afonso AM, Roche B, et al. Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 2008;47: Duclos-Vallee JC, Vittecoq D, Teicher E, Feray C, Roque- Afonso AM, Lombes A, et al. Hepatitis C virus viral recurrence and liver mitochondrial damage after liver transplantation in HIV-HCV co-infected patients. J Hepatol 2005;42: de Vera ME, Dvorchik I, Tom K, Eghtesad B, Thai N, Shakil O, et al. Survival of liver transplant patients coinfected with HIV and HCV is adversely impacted by recurrent hepatitis C. Am J Transplant 2006;6: Hammer SM, Eron JJ Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008;300: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. November 3, Available at: adultandadolescentgl.pdf. Accessed April Rivero A, Mira JA, Pineda JA. Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors. J Antimicrob Chemother 2007;59: Sulkowski M, Thomas D, Mehta S, Chaisson R, Moore R. Hepatotoxicity associated with nevirapine or efavirenzcontaining antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002;35:

7 1342 TEICHER ET AL. 11. Martin-Carbonero L, Nuñez M, Gonzalez-Lahoz J, Soriano V. Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV Clin Trials 2003; 4: Martinez E, Blanco J, Arnaiz J, Perez-Cuevas J, Mocroft A, Cruceta A. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS 2001;15: Hicks C, King MS, Gulick RM, White AC Jr, Eron JJ Jr, Kessler HA, et al. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study. AIDS 2004;18: Kempf DJ, Isaacson JD, King MS, Brun SC, Sylte J, Richards B, et al. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antivir Ther 2002;7: Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clin Infect Dis 2004;38(suppl 2):S90 S Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995;13: Benet LZ, Izumi T, Zhang Y, Silverman JA, Wacher VJ. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Control Release 1999;62: Cummins CL, Salphati L, Reid MJ, Benet LZ. In vivo modulation of intestinal CYP3A metabolism by P-glycoprotein: studies using the rat single-pass intestinal perfusion model. J Pharmacol Exp Ther 2003;305: King JR, Wynn H, Brundage R, Acosta EP. Pharmacokinetic enhancement of protease inhibitor therapy. Clin Pharmacokinet 2004;43: Jain AB, Venkataramanan R, Eghtesad B, Marcos A, Ragni M, Shapiro R, et al. Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients. Liver Transpl 2003;9: Teicher E, Vincent I, Bonhomme-Faivre L, Abbara C, Barrail A, Boissonnas A, et al. Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C virus and HIV co-infected liver transplant recipients in the ANRS HC-08 study. Clin Pharmacokinet 2007;46: Frassetto LA, Browne M, Cheng A, Wolfe AR, Roland ME, Stock PG, et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant 2007;7: Vogel M, Voigt E, Michaelis HC, Sudhop T, Wolff M, Turler A, et al. Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ ritonavir in liver-transplanted HIV-infected patients. Liver Transpl 2004;10: Frassetto L, Baluom M, Jacobsen W, Christians U, Roland ME, Stock PG, et al. Cyclosporine pharmacokinetics and dosing modifications in human immunodeficiency virusinfected liver and kidney transplant recipients. Transplantation 2005;80: Boffito M, Acosta E, Burger D, Fletcher CV, Flexner C, Garaffo R, et al. Therapeutic drug monitoring and drugdrug interactions involving antiretroviral drugs. Antivir Ther 2005;10: Izzedine H, Launay-Vacher V, Baumelou A, Deray G. Antiretroviral and immunosuppressive drug-drug interactions: an update. Kidney Int 2004;66: Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003;348: Nelson M, Arasteh K, Clotet B, Cooper DA, Henry K, Katlama C, et al. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr 2005; 40: Hardy H, Skolnik PR. Enfuvirtide, a new fusion inhibitor for therapy of human immunodeficiency virus infection. Pharmacotherapy 2004;24: Poveda E, Briz V, Soriano V. Enfuvirtide, the first fusion inhibitor to treat HIV infection. AIDS Rev 2005;7: Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997;25: Da Silva B, King M, Cernohous P. Lopinavir/ritonavir safety, tolerability and efficacy in hepatitis C and/or hepatitis B infected patients: review of clinical trials. Paper presented at: 15th International AIDS Conference; 2004; Bangkok, Thailand. 33. Chihrin S, Antoniou T, Raboud J, Shen S, Govan V. Risk factors for grade 3-4 liver enzyme elevation in HIV and hepatitis C coinfected patients on combination antiretroviral therapy. AIDS Patient Care STDS 2007;21: