Influence of liver fibrosis stage on plasma levels of efavirenz in HIV-infected patients with chronic hepatitis B or C

Transcription

1 Journal of Antimicrobial Chemotherapy Advance Access published January 23, 2009 Journal of Antimicrobial Chemotherapy doi: /jac/dkn531 Influence of liver fibrosis stage on plasma levels of efavirenz in HIV-infected patients with chronic hepatitis B or C Jean-Luc Meynard 1 *, Karine Lacombe 1, Jean-Marie Poirier 2, Jennifer Legrand 3, Laurence Morand-Joubert 4 and Pierre-Marie Girard 1 1 Service des Maladies Infectieuses et Tropicales, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France; 2 Service de Pharmacologie, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France; 3 Service de Pharmacie, Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Clichy, France; 4 Service de Bactériologie-Virologie, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France Received 6 August 2008; returned 12 September 2008; revised 9 December 2008; accepted 12 December 2008 Objectives: Liver function is a key component of efavirenz metabolism and might be altered in severe liver fibrosis induced by HIV/chronic hepatitis co-infection. However, data evaluating the impact of liver fibrosis stages on the plasma efavirenz level are lacking. Patients and methods: In this study, conducted in 134 HIV-infected patients [77, 35 and 22 HIV monoinfected, HIV/hepatitis C virus (HCV) co-infected and HIV/hepatitis B virus (HBV) co-infected, respectively] treated with efavirenz 600 mg once a day in combination with other antiretroviral agents, plasma concentration was measured at least 8 h after the last drug intake using a validated HPLC method. The degree of liver fibrosis was determined by means of either liver biopsy or non-invasive biochemical markers (Fibrotest w ). The proportions of patients above a threshold of 4000 ng/ml were compared by means of Pearson s x 2 test or Fisher s exact test. Results: In HIV mono-infected and HIV/HCV and HIV/HBV co-infected patients, mean +SD efavirenz plasma concentrations were , and ng/ml, respectively. The proportion of patients with an efavirenz concentration above 4000 ng/ml differed significantly according to the presence of hepatitis and the fibrosis stage. A concentration above 4000 ng/ml was found in 14 patients (18.2%) mono-infected with HIV compared with 5 (22.7%, P ) and 9 (25.7%, P ) HIV/HBV or HIV/HCV co-infected patients, respectively. When the fibrosis stage was considered in all patients with hepatitis, 3 cirrhotic patients (42.6%) had an efavirenz concentration above the 4000 ng/ml threshold [compared with 14 (18.2%) HIV mono-infected patients, P ]. Conclusions: Therapeutic drug monitoring may be of interest in cirrhotic patients more at risk of side effects due to efavirenz overdosing. Keywords: antiretrovirals, drug monitoring, tolerance Introduction HAART has dramatically improved the natural course of HIV infection. However, the long-term use of antiretroviral therapy has been associated with the occurrence of severe complications. Recent studies highlight that hepatic events have become one of the main causes of mortality and morbidity in HIV-infected patients. 1,2 Almost all antiretroviral drugs currently in use may cause elevations in liver enzyme levels and the mechanisms involved vary widely. 3 Nevertheless, most cohort studies show that co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is a significant risk factor for increase in liver enzyme levels 4 6 and is associated with a higher probability of severe liver fibrosis. 7 Furthermore, liver function is a key component of drug metabolism and might be altered in severe liver fibrosis induced by hepatic co-infection. 8 Although HCV or HBV co-infections are frequently observed in HIV-infected patients, data evaluating the impact of liver fibrosis stage on plasma levels of drugs are lacking. To our knowledge, only one recent study has investigated the role of liver fibrosis severity in... *Corresponding author. jean-luc.meynard@sat.ap-hop-paris.fr... Page 1 of 6 # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Meynard et al. antiretroviral drugs plasma concentration but focused on HIV/HCV co-infected patients. 9 The results were also subject to caution because non-compliant patients with very low drug plasma levels were included in the analysis. Efavirenz is a widely used non-nucleoside reverse transcriptase inhibitor (NNRTI) that has become a cornerstone of antiretroviral combination regimens. 10 Unlike nevirapine for which hepatotoxicity is clearly documented, 11 the association between efavirenz and hepatotoxicity is still debated. Recent studies indeed showed that the occurrence of elevated liver enzymes during the first 6 weeks following introduction of efavirenz was correlated to the exposure of efavirenz. 12 Moreover, it has been suggested that a concentration of efavirenz above 4000 ng/l might be a risk factor for pronounced neurotoxic effects. 13 The liver clearance of NNRTIs, particularly efavirenz, might also be impaired in HIV/HCV co-infected patients with cirrhosis. 13 The purpose of the present study was to assess whether efavirenz plasma levels differed according to fibrosis stages in HIVinfected patients with chronic hepatitis B or C. Patients and methods Between April 2003 and February 2004, all HIV-1-infected patients regularly seen at our 2500 patient HIV department were eligible for the present study if an efavirenz-containing regimen was initiated. All patients gave their written consent to participate in the study, according to the Helsinki declaration. Demographic data, HIV history and prior antiretroviral treatment history were derived from the electronic database of the department. Pre-treatment sera were tested for HCV antibody, HBs antigen and antibody, HBe antigen and antibody (HBV) and hepatitis D antibody (HDV) using commercial ELISA assays. HCV-RNA and HBV-DNA were quantified when appropriate. Three mutually exclusive groups of patients were defined upon the results of those tests: (i) patients with negative HCV serology and HCV-RNA under the detection limit and with negative serum HBs antigen and HBV-DNA under the detection limit were classified as HIV alone; (ii) patients with positive HCV serology, negative serum HBs antigen and HBV-DNA under the detection limit were classified as HIV/HCV; and (iii) patients with positive serum HBs antigen, negative HCV serology and PCR HCV under the detection limit were classified as HIV/HBV. Patients with dual or triple hepatitis co-infection (i.e. HBV/HCV, HBV/HDV or HBV/HCV/HDV) were excluded. Biochemical, immunological and virological data were assessed at treatment initiation. Plasma efavirenz dosage was performed within 6 months of treatment introduction. CD4 lymphocyte count was determined by flow cytometry. Plasma HIV load was measured with the branched-dna technique (b-dna Quantiplex 3.0 Bayer Diagnostics w, Cergy Pontoise, France, detection limit 50 copies/ml). HBV load DNA was quantified with a commercial PCR-based assay (Cobas Amplicor w HBV monitor, Roche Diagnostic Systems, Meylan, France, detection limit 60 IU/mL). HCV-RNA was detected by a sensitive commercial PCR-based assay (Cobas Amplicor w HCV v2.0. Roche Diagnostic Systems, detection limit 60 IU/mL) and quantified, when positive, by the branched-dna technique (Versant HCV-RNA 3.0. assay w, Bayer Diagnostics). Plasma efavirenz assays were done in a central pharmacology laboratory, using an HPLC method with a detection limit of 10 ng/ml. Trough (C min ) plasma levels were recorded h after the last drug intake. The degree of liver fibrosis was determined by means of either liver biopsy or non-invasive biochemical markers (Fibrotest w ). All biochemical markers were measured in sera collected on the date of patients inclusion and liver biopsy was performed within 1 year. Liver biopsy samples were stained with haematoxylin/phloxin/ saffran and Picrosirius Red, and histological fibrosis was scored using the METAVIR classification (Bedossa). The calculation of the Fibrotest w score was based on measures of total bilirubin, gammaglutamyl-transferase (ggt), a2-macroglobulin, apolipoprotein A1 and haptoglobin, adjusted for age and sex (Poynard). Total bilirubin and ggt were measured using an autoanalyser (Olympus AU640, Tokyo, Japan) and were calibrated on CFAS (Calibrator for Automated Systems, Roche Diagnostic). a2-macroglobulin, apolipoprotein A1 and haptoglobin were measured using an automatic nephelometer (BNII, Dade Behring, Marburg, Germany). The transferability of the results obtained with these analytical methods was validated for Fibrotest w calculation by the Biopredictive company (Paris, France). Biochemical scores were not assessed in the case of suspicion of Gilbert s Disease or use of the HIV protease inhibitor atazanavir [bilirubin.17 mmol/l and alanine aminotransferase (ALT),30 IU/mL], haemolytic anaemia (haptoglobin,0.3 g/l) or acute inflammation (haptoglobin.2 g/l). All statistical analyses were done with SPSS software version 11.5, using 0.05 as a P threshold for significance. Categorical data were analysed with Pearson s x 2 test or Fisher s exact test when appropriate. Continuous variables were compared using a two-tailed t-test using least-square mean values when variables were normally distributed or Mann Whitney test otherwise. The Wilcoxon ranked-test was used for paired continuous data analysed over time, and efavirenz plasma concentration was analysed as a dichotomized variable using the threshold of 4000 ng/ml. This threshold is considered to be associated with an increased risk of neurotoxic effects. 13 Only patients with an efavirenz plasma concentration above 1000 ng/ml, thus supposedly adherent to treatment, were considered for the purpose of the final analysis. Results Patient characteristics A total of 134 patients (101 males) were included in the study; 77 in the HIV group, 22 in the HIV/HBV group and 35 in the HIV/HCV group. General characteristics of the study population are described in Table 1. The three most frequent antiretrovirals concomitantly prescribed with efavirenz 600 mg once a day were lamivudine (n ¼ 71; 53%), didanosine (n ¼ 46; 34%) and tenofovir (n ¼ 33; 25%). In 34 patients, a protease inhibitor was associated with efavirenz [53% (n ¼ 18) lopinavir boosted with ritonavir]. No patient was treated for HCV infection during the study time, whereas 59% of HBV-infected patients were receiving drugs with a dual anti-hiv and anti-hbv activity (lamivudine and/or tenofovir). None was treated with interferon. In two HCV-infected patients, liver fibrosis could not be assessed. The level of fibrosis in the remaining 55 hepatitis co-infected patients was determined by means of liver biopsy and Fibrotest in 30 and 25 patients, respectively. The distribution of METAVIR scores was as follows: F0, 14; F1, 18; F2, 8; F3, 7; F4, 8. Three of the eight patients with an F4 score had at least one episode of decompensated cirrhosis before efavirenz introduction. The efavirenz dosage was performed after a median duration of efavirenz-containing regimen of 1.7 months (IQR: ). The results showed a concentration of efavirenz below 1000 ng/ml Page 2 of 6

3 Table 1. Patients characteristics according to hepatitis subgroups Page 3 of 6 Total, n ¼ 134 HIV, n ¼ 77 HIV/HBV, n ¼ 22 HIV/HCV, n ¼ 35 Sex ratio (male/female) 101/33 60/17 17/5 24/11 Age, years (mean, SD) 41.1 (8.9) 41.9 (10.6) 39.1 (7.1) 40.6 (39.6) HIV duration, years (mean, SD) a 8.0 (5.5) 7.1 (5.6) 7.7 (5.1) 10.2 (5.1) HBV duration, years (mean, SD) a 3.0 (3.7) 3.0 (3.7) HCV duration, years (mean, SD) a 2.6 (2.9) 2.6 (2.9) CDC stage C (n, %) 49 (36.6) 31 (40.3) 6 (27.3) 12 (34.3) Concomitant PI (n, %) 34 (25.4) 21 (27.3) 3 (13.6) 10 (28.6) EFV duration before dosage, months (median, IQR) 1.7 ( ) 1.6 ( ) 2.3 ( ) 1.5 ( ) EFV concentration, ng/ml (mean, SD) 3162 (2434) 2960 (1954) 3059 (2422) 3673 (3262) Patients under 1000 ng/ml (n, %) 7 (5.2) 3 (3.9) 1 (4.5) 3 (8.6) Patients above 4000 ng/ml (n, %) 28 (20.9) 14 (18.2) 5 (22.7) 9 (25.7) CD4 cell count at EFV dosage, log 10 copies/ml (mean, SD) 396 (244) 401 (272) 424 (217) 367 (196) HIV-RNA at EFV dosage, cells/mm 3 (median, IQR) 1.69 ( ) 1.91 ( ) 1.69 ( ) 1.76 ( ) ALT at EFV initiation (mean, SD) 41 (36) 35 (36) 44 (37) 52 (33) AST at EFV initiation (mean, SD) 40 (59) 35 (71) 33 (17) 53 (41) ALT at EFV dosage (mean, SD) 49 (57) 41 (54) 50 (46) 68 (68) AST at EFV dosage (mean, SD) 40 (39) 30 (19) 35 (22) 65 (63) Efavirenz and liver fibrosis HBV, hepatitis B virus; HCV, hepatitis C virus; PI, protease inhibitor; EFV, efavirenz; ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Duration of infection estimated from the date of first positive serology. Downloaded from at Pennsylvania State University on May 11, 2016

4 Meynard et al. (range: ) in 7 patients and above 4000 ng/ml in 28 patients (range: ). At efavirenz initiation, ALT was significantly higher in the HIV/HCV group compared with HIV alone (52 versus 35 IU/mL, P,0.05). However, transaminase means were not significantly different between groups at the time of efavirenz dosage (Table 1). Efavirenz concentrations The efavirenz concentrations according to co-infection groups and METAVIR stages are reported in Table 2. They were similar in the HIV and HBV groups (3060 versus 3163 ng/ml, P ¼ 0.8), and there was a trend towards a higher concentration in HCV patients compared with HIV alone (4108 versus 3060 ng/ml, P ¼ 0.08). The proportion of patients with an efavirenz concentration above 4000 ng/ml differed significantly according to the presence of hepatitis and the fibrosis stage (Figure 1). A concentration above 4000 ng/ml was found in 14 (18.2%) patients with HIV compared with 5 (22.7%) patients with HBV (P ¼ 0.01) and 9 (25.7%) patients with HCV (P ¼ 0.001). When the fibrosis stage was considered, 3 (42.6%) cirrhotic patients had an efavirenz concentration above the 4000 ng/ml threshold [compared with 14 (18.2%) HIV monoinfected patients, P ¼ 0.001]. Discussion HIV-1-specific NNRTIs, such as nevirapine or efavirenz, are frequently used in combination with other antiretroviral drugs for the treatment of HIV infection. Even if several studies showed that chronic hepatitis enhances the risk of drug-related hepatotoxicity, the influence of the liver fibrosis stage and plasma drug level is still debated and seems notably to depend on the drug studied. To our knowledge, no data comparing three groups of patients, HIV without co-infection, HIV/HBV and HIV/HCV, have been reported to date. In our population, we did not find a plasma drug concentration of efavirenz significantly different between the three groups studied, although a tendency towards higher plasma trough concentration was suggested in the HIV/HCV group. Of note, a higher proportion of HIV/HCVinfected patients had active hepatitis disease with viral replication compared with HIV/HBV co-infected patients. An absence of viral suppression may lead to increased necrotico-inflammatory activity in the liver. This induces a progressive alteration of liver function, which in turn may cause a defect in drug metabolism. In order to better understand the relationship between plasma efavirenz concentration and viral hepatitis co-infection, we have explored the association between the stage of liver fibrosis in co-infected patients and the risk of having an efavirenz plasma drug level above 4000 ng/ml. This threshold was chosen because it had been associated in previous studies with central nervous system side effects. 13 This value was more frequently reached in patients with co-infection and the percentage of patients above this level also increased with the level of fibrosis (e.g. 42.6% of patients with a fibrosis score of F4 presented with a concentration of efavirenz above that value). The metabolism of efavirenz in the liver might thus be sensitive to the impairment of liver function, particularly in cirrhotic patients. Our results are in accordance with those concerning cirrhotic patients in a study recently published by Barreiro et al. 9 In this study, Table 2. Efavirenz concentrations according to co-infection groups and METAVIR stages No co-infection, n ¼ 74 HBV or HCV co-infection, n ¼ 51 HBV, n ¼ 21 HCV, n ¼ 30 Cmin (mean, SD) 3060 (1928) 3719 (2999) 3163 (2432) 4108 (3324) METAVIR stages F0 F3, n ¼ 44 F4, n ¼ 7 F0 F3, n ¼ 18 F4, n ¼ 3 F0 F3, n ¼ 26 F4, n ¼ 4 Cmin (mean, SD) 3639 (3031) 4221 (2962) 3173 (2595) 3105 (1387) 3961 (3310) 5059 (3753) C min, minimal concentration; HBV, hepatitis B virus; HCV, hepatitis C virus. Page 4 of 6

5 Efavirenz and liver fibrosis Patients in each group (%) P < 0.01* P < 0.001* Patients in each group (%) P < 0.001* HIV HBV HCV Co-infection groups which included 46 HIV/HCV co-infected patients, efavirenz plasma levels above this threshold were more frequent in patients with cirrhosis than in those without (31% versus 3%; P, 0.001). A positive correlation between levels of fibrosis and plasma drug efavirenz levels was also found. However, the analysis also included, in the non-cirrhotic group, three patients with efavirenz plasma levels of,1000 ng/ml. These values are only observed in non-compliant patients who should have been considered separately in the analysis as we did in our study. Finally, the relationship between NNRTI plasma levels and the risk of liver toxicity has been subject to debate. 5 In our study, ALT was significantly higher in the HIV/HCV group compared with HIV alone only at baseline, before efavirenz prescription. Our study has several limitations. Factors that may influence efavirenz plasma levels such as genetic factors ( polymorphism gene CYP2B6) 14 were not analysed. Because of the study design, we could neither accurately record efavirenz tolerance, particularly in patients above the threshold of 4000 ng/ml, nor evaluate efavirenz adherence. However, patients with a suboptimal concentration (,1000 ng/ml), which was considered as a surrogate marker of non-adherence, were excluded from the final analysis. The low number of cirrhotic patients in the co-infected groups could be responsible for the lack of power to detect an increasing association between plasma drug concentration and the co-infection groups according to the level of fibrosis. Scarce data on interaction between efavirenz and low-dose ritonavir administered as a protease inhibitor booster have also been reported, but because of the conflicting nature of the results, it is difficult to assess the risk of efavirenz overdosage linked with low-dose ritonavir. In conclusion, plasma efavirenz concentration was not increased in HIV/hepatitis co-infected patients without cirrhosis. No dosing adjustment may therefore be required in this population. However, plasma efavirenz monitoring may be performed in cirrhotic patients in whom there is a higher risk of efavirenz 10 0 concentration above 4000 ng/l and therefore a higher prevalence of CNS side effects, which could have a negative impact in terms of tolerance and compliance to treatment. Funding No funding has been received from pharmaceutical firms to conduct this study. Biochemical tests were performed with funds received from Sidaction, a French foundation providing funding for research programmes on HIV/AIDS. Transparency declarations None to declare. References NA F0 F3 F4 Liver fibrosis Figure 1. Proportion of patients with efavirenz concentration.4000 ng/ml according to co-infection groups and level of liver fibrosis. HIV, HIV infection without chronic hepatitis; HBV, HIV infection with chronic hepatitis B; HCV, HIV infection with chronic hepatitis C; NA, not applicable (HIV infection only); F0 F4, METAVIR fibrosis scores 0 to 4. *Fisher s exact test. 1. Palella FJ Jr, Baker RK, Moorman AC et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43: Waeber R, Sabin C, Friis-Moller N et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006; 166: Nunez M. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. J Hepatol 2006; 44: Sulkowski MS, Thomas DI, Mehta S et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002; 35: Law WP, Dore GJ, Duncombe CJ et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand AIDS 2003; 17: Page 5 of 6

6 Meynard et al. 6. Servos JC, Kitch DW, Andersen JW et al. Predictors of antiretroviral-related hepatotoxicity in the Adult AIDS Clinical Trial Group ( ). J Acquir Immune Defic Syndr 2006; 43: Aranzabal L, Casado JL, Moya J et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 2005; 40: Farye R, Zgheib N, Matzke G et al. Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther 2006; 80: Barreiro P, Rodríguez-Novoa S, Labarga P et al. Influence of liver fibrosis stage on plasma levels of antiretroviral drugs in HIV-infected patients with chronic hepatitis C. J Infect Dis 2007; 195: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services, 29 January 2008; AdultandAdolescentGL.pdf (2 October 2008, date last accessed). 11. Sanne I, Mommeja-Marin H, Hinkle J et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005; 191: Kappelhoff BS, van Leth F, Robinson PA et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 2005; 10: Marzolini C, Telenti A, Decosterd LA et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001; 15: King J, Aberg JA. Clinical impact of patient population differences and genomic variation in efavirenz therapy. AIDS 2008; 22: Page 6 of 6