Antiviral Therapy 2013; 18: (doi: /IMP2483)

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1 Antiviral Therapy 2013; 18: (doi: /IMP2483) Short communication Plasma concentrations of efavirenz with a 600 mg standard dose in Cambodian HIV-infected adults treated for tuberculosis with a body weight above 50 kg Laurence Borand 1, Didier Laureillard 2, Yoann Madec 3, Monidarin Chou 4, Phearavin Pheng 1, Olivier Marcy 1, Thim Sok 5, Anne E Goldfeld 5,6, Anne-Marie Taburet 7, François-Xavier Blanc 8 *, the CAMELIA (ANRS 1295 CIPRA KH001) study team 1 Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia 2 ANRS, Ho Chi Minh City, Vietnam 3 Unité de Recherche et d Expertise Epidémiologie des Maladies Emergentes, Institut Pasteur, Paris, France 4 Faculty of Pharmacy, University of Health Sciences, Phnom Penh, Cambodia 5 Cambodian Health Committee, Phnom Penh, Cambodia 6 Immune Disease Institute, Harvard Medical School, Boston, MA, USA 7 Clinical Pharmacy Department, Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Le Kremlin- Bicêtre, France 8 Pneumology Department, Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Le Kremlin- Bicêtre, France *Corresponding author xavier.blanc@bct.aphp.fr Background: The optimal dose of efavirenz for HIVinfected patients receiving a tuberculosis regimen including rifampicin remains debated, especially for subjects weighing over 50 kg. To address this issue, we measured plasma efavirenz concentrations from Cambodian adults with tuberculosis enrolled in the CAMELIA randomized trial (ClinicalTrials.gov number, NCT ) 6 weeks after the onset of antiretroviral therapy. Methods: Efavirenz concentrations and proportions of patients with concentrations below 1,000 ng/ml were compared across patient body weight below or above 50 kg using a Student s t-test and a c 2 test, respectively. Factors associated with efavirenz concentrations below 1,000 ng/ml were identified by logistic regression analysis. Logistic regression analysis was also performed to check if efavirenz concentrations below 1,000 ng/ml were associated with virological failure. Results: Plasma efavirenz concentrations were higher in the 332 patients who weighed <50 kg compared with the 150 who weighed 50 kg (median [IQR] 2,859 [1,787 4,749] and 2,060 [1,425 3,575] ng/ml, respectively; P=0.02). However, the proportion of patients with efavirenz concentrations below 1,000 ng/ml was not different between those weighing less than or more than 50 kg (6% and 10%, respectively; P=0.13) and a body weight above 50 kg was not associated with a higher risk of plasma efavirenz concentrations below 1,000 ng/ml. When plasma efavirenz concentrations below 1,000 ng/ml were present, they were not associated with virological failure. Conclusions: The current WHO guidelines recommending 600 mg efavirenz daily irrespective of patient s body weight remains a safe and effective approach to treating coinfected adults needing simultaneous tuberculosis and HIV therapy. Introduction Efavirenz (EFV) is the preferred non-nucleoside reverse transcriptase inhibitor for HIV-infected patients starting antiretroviral therapy (ART) while on tuberculosis treatment. However, the optimal dosage of EFV during coadministration of tuberculosis treatment has remained a point of debate [1]. Current recommendations vary according to guidelines from using 600 mg EFV daily in HIV-infected adults receiving rifampicin, irrespective of body weight (BW) [2], to an increased daily dose of 800 mg EFV 2013 International Medical Press (print) (online) 419

2 L Borand et al. when the patient s BW is above 50 kg [3,4] or above 60 kg [5,6]. Here, we report plasma EFV concentrations measured 6 weeks after ART initiation in HIV-infected adults included in the CAMELIA (Cambodian Early versus Late Introduction of Antiretrovirals; NCT ) trial [7] with a BW < or 50 kg, all of whom received a daily dose of 600 mg of EFV concomitantly with tuberculosis therapy including rifampicin. We also evaluated whether a BW of 50 kg was a risk factor associated with plasma EFV concentrations below 1,000 ng/ml. Methods The CAMELIA trial was designed to determine the optimal timing of ART initiation after tuberculosis treatment onset in severely immunocompromised (CD4 + T-cell count 200 cells/mm 3 ) HIV-1-infected adults who were ART-naive and had newly diagnosed smear-positive tuberculosis [7]. It was conducted in accordance with the Declaration of Helsinki and approved by the Cambodian National Ethics Committee on Health Research and the ethics review boards of the Immune Disease Institute and Médecins sans Frontières. Each patient signed the informed consent form prior to inclusion. Tuberculosis treatment consisted of a daily regimen of rifampicin (10 mg/kg), isoniazid (4 5 mg/kg), ethambutol (15 20 mg/kg) and pyrazinamide (20 30 mg/kg) for 2 months, followed by rifampicin (10 mg/kg/day) and isoniazid (4 5 mg/ kg/day) for 4 months. ART, including stavudine (30 mg twice daily), lamivudine (150 mg daily) and EFV (600 mg daily), was initiated 2 or 8 weeks after the onset of tuberculosis therapy depending on study arm. EFV concentrations were measured in plasma samples drawn 14 ±2 h after EFV intake 6 weeks after ART initiation (W+6) in each study arm. All samples were assayed using a validated high-performance liquid chromatography technique. The lower limit of quantification was 50 ng/ml. All concentrations below the limit of quantification were set to 50 ng/ml in this analysis. Within and between day variability of the assay were below 15%. The therapeutic range of EFV was considered to be 1,000 4,000 ng/ml as previously described [8]. Mean EFV concentrations and proportions of patients with EFV concentrations below 1,000 ng/ml were compared across patient BW < or 50 kg using a Student s t-test and a c 2 test, respectively. A logistic regression analysis was performed to identify factors associated with EFV concentrations below 1,000 ng/ ml, as opposed to concentrations above. Other than BW < or 50 kg at ART initiation and at sampling time, factors considered in the analysis were study site, study arm, gender, age, body mass index, tuberculosis location, CD4 + T-cell count, HIV RNA, haemoglobin, aspartate aminotransferase (AST), alanine aminotransferase and late attendance to W+6 study visit defined as attending the study visit with a delay >2 days. In addition, a logistic regression analysis was performed to check if EFV concentrations below 1,000 ng/ml were associated with virological failure defined as plasma HIV RNA>250 copies/ml measured between 18 and 24 weeks from ART initiation. Results Among the 661 patients of the CAMELIA trial, 482 received EFV and had a blood sample drawn 14 ±2 h after EFV intake 6 weeks after ART onset. The remaining 179 patients were not considered in the analysis for the following reasons: 31 were from a study site where samples could not be drawn in the appropriate time window; 51 patients died before W+6; 1 withdrew; 16 did not attend the visit; 45 were not receiving EFV at W+6; 10 did not have blood sampling at W+6; and 25 had no EFV measurement within 14 ±2 h post- EFV ingestion. At ART initiation, mean BW was 45.6 kg (sd 8.0) and 150 (31%) patients weighed 50 kg. This higher weight group included a larger proportion of men (93% versus 53%; P<0.001) and more patients enrolled in the later- ART initiation study arm (61% versus 40%; P<0.001). Neither CD4 + T-cell count (P=0.65) nor plasma HIV RNA levels (P=0.50) were different between patients weighing < and 50 kg (median [IQR] CD4 + T-cell count 24 [12 57] and 28 [12 62] cells/ml, respectively; median [IQR] plasma HIV RNA levels 5.6 [ ] and 5.6 [ ] log 10 copies/ml, respectively). By contrast, haemoglobin level at ART initiation was lower in patients weighing <50 kg compared with those weighing 50 kg (median [IQR] 94 [79 109] versus 112 [ ] g/l, respectively; P<0.001). The proportion of patients with AST<1.25 the upper limit of normal was significantly higher in patients weighing 50 kg compared with those weighing <50 kg (62% versus 40%, respectively; P<0.001). Six weeks after ART initiation, the median (IQR) plasma EFV concentration was 2,649 (1,704 4,467) ng/ml. Overall, 35 (7%) patients had plasma EFV concentrations below 1,000 ng/ml and 11 (2%) had concentrations below 50 ng/ml. As shown in Figure 1, plasma EFV concentrations were significantly higher in patients weighing <50 kg compared with those weighing 50 kg (median [IQR] 2,859 [1,787 4,749] and 2,060 [1,425 3,575] ng/ml, respectively; P=0.02). However, the proportion of patients with EFV concentrations below 1,000 ng/ml was not different between those weighing < and 50 kg (6% and 10%, respectively; P=0.13). Of note, 22% of patients who weighed International Medical Press

3 Efavirenz 600 mg standard dose in adults with tuberculosis Figure 1. Box plots of plasma EFV concentrations 6 weeks after ART onset in patients weighing <50 kg a and 50 kg b EFV plasma concentration, ng/ml 40,000 30,000 20,000 10,000 0 <50 kg 50 kg a Grey box, n=332. b Clear box, n=150. Dashed lines represent the efavirenz (EFV) alleged therapeutic range: 1,000 4,000 ng/ml. ART, antiretroviral therapy. 50 kg had EFV concentration above 4,000 ng/ml and 9% had a concentration greater than 8,000 ng/ml. In univariate analysis, a BW 50 kg as compared with BW<50 kg while receiving rifampicin-based tuberculosis therapy at ART initiation did not increase the risk of having a plasma EFV concentration below 1,000 ng/ml (OR [95% CI] 1.73 [0.86, 3.49]; P=0.13). Similarly, BW 50 kg or <50 kg at the time of sampling was not associated with plasma EFV concentration below 1,000 ng/ml (OR [95% CI] 1.36 [0.67, 2.75]; P=0.40). The only factor significantly associated with an increased risk of EFV concentration below 1,000 ng/ml was late attendance at the W+6 protocol visit (OR [95% CI] 8.11 [2.25, 29.21], P=0.005). Because the proportion of patients weighing 50 kg was higher in the later-art initiation study arm than in the earlier-art arm, we investigated whether the effect of BW was the same across study arms and found no such evidence (interaction test: P=0.32). In a sensitivity analysis, we excluded the 11 EFV concentrations below the limit of quantification, which likely reflected lack of adherence. Even when excluding these patients, BW 50 kg at ART initiation was not associated with an increased risk of EFV concentration below 1,000 ng/ ml (P=0.11). Among the 446 patients with HIV RNA level available between 18 and 24 weeks from ART initiation, 42 (9.4%) had an HIV RNA>250 copies/ml, including 4 patients with EFV concentration below 1,000 ng/ml at W+6. Notably, in univariate analysis, neither EFV below 1,000 ng/ml nor BW 50 kg were significantly associated with virological failure (P=0.43 and P=0.11, respectively). Discussion These pharmacokinetic data from a large number of HIV tuberculosis-coinfected adults enrolled in a randomized clinical trial showed that a BW 50 kg at ART initiation was not associated with an increased risk of plasma EFV concentrations below 1,000 ng/ ml in patients receiving a daily dose of 600 mg EFV and concomitant rifampicin-based tuberculosis therapy. We used 1,000 ng/ml as a point of reference because some have suggested this to be a therapeutic threshold, although data to support such a threshold are scant [8]. Our findings are supported by several clinical studies [9 11]. In a study conducted in 42 Thai patients (average BW 50.6 kg) who received 600 mg EFV daily along with rifampicin, only 7.9% of patients had EFV plasma concentrations below 1,000 ng/ml, which is close to our findings [9]. Two other studies have demonstrated no statistical difference in median plasma EFV concentrations in patients weighing less than 60 kg as compared with patients weighing >60 kg who received a daily dose of 600 mg EFV while taking rifampicin [10,11]. Other authors have found that EFV plasma levels were not predicted by BW in patients with a mean BW of 59.4 kg [12]. By contrast, a pharmacokinetic simulation model and two pharmacokinetic studies involving a relatively small number of patients supported the increase in EFV dosing to 800 mg/day to compensate for the effect of rifampicin when a patient s BW was over 50 kg [13 15]. In our study, virological failure was not associated with BW 50 kg or with EFV plasma concentrations below 1,000 ng/ml. This is consistent with findings from the N 2 R study that demonstrated no statistical difference in the proportion of patients with undetectable plasma HIV RNA levels who took a daily dose of 600 mg EFV as compared with 800 mg EFV together with rifampicin at 48 weeks of post-treatment initiation [16]. Furthermore, other data showed an association between neurotoxicity and high EFV serum concentrations in patients with a BW over 50 kg who received 800 mg of EFV along with rifampicin [17]. Plasma concentration of EFV was above 4,000 ng/ ml in 22% of patients with a BW 50 kg. It is now well-established that patients carrying the CYP2B6 516 TT genetic polymorphism have higher concentrations of EFV [18]. Chou et al. [19] have reported the frequency of the loss of function allele in Cambodian population with an average value of 35%. We can speculate that such a high frequency of the CYP2B6 516G_T mutant allele in Cambodians could explain, at least in part, the high observed concentrations of Antiviral Therapy

4 L Borand et al. EFV in a subset of our study population. We cannot exclude that an unlikely unrecognized imbalance between proportions of genotypes between patients with a BW 50 kg and <50 kg could exist and influence our results. Another limitation of our study is that we did not measure EFV concentrations at trough times, that is, 10 h later, mostly because of bedtime drug intake. However, it has been found that EFV plasma levels were only slightly influenced by the sampling time [8] and that EFV half-life is as long as 49 h [20], that is, much longer than the 10 h interval separating mid-dose from trough time. Thus, we speculate that our results would not markedly differ if we have used trough time concentrations. These studies taken together with our data lead us to conclude that the current WHO guidelines recommending a daily dose of 600 mg EFV irrespective of the patients BW remains a safe and effective approach to treating coinfected adults needing simultaneous tuberculosis and HIV therapy. Acknowledgements The authors are grateful to the patients who accepted to participate to this study and to the patients representatives who contributed to the information sheet and consent form writing. They are grateful to the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and the US National Institutes of Health Division of AIDS who both funded the CAMELIA clinical trial and to the Rodolphe Mérieux Foundation for the collaboration on the pharmacokinetics assays. The authors would also like to acknowledge the CAMELIA teams from the study sites, Cambodian Health Committee, Institut Pasteur du Cambodge, and Médecins Sans Frontières Belgium for their active contribution to the trial. This work was supported by the ANRS (study number 1295) and the US National Institutes of Health Division of AIDS (CIPRA KH001). Disclosure statement LB, DL, OM, TS, AEG, A-MT and F-XB have received a grant (number 1295) from ANRS and the US National Institutes of Health Division of AIDS (number CIPRA KH001) to conduct this study. AEG has served as a consultant for the AERAS Global Vaccine Foundation, which provided funds to the Cambodian Health Committee to conduct studies. A-MT has received honoraria from Gilead and travel/accommodations/meeting expenses not related to this study from Janssen. F-XB has received travel/accommodations/meeting expenses not related to this study from Astra-Zeneca, GSK and Novartis. All other authors declare no competing interests. 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