Infection DOI 10.1007/s15010-014-0599-z
CASE REPORT
Pharmacokinetics of etravirine in HIV-infected patients concomitantly treated with rifampin for tuberculosis R. Gagliardini • M. Fabbiani • S. Fortuna • E. Visconti P. Navarra • R. Cauda • M. Colafigli • A. De Luca • E. M. Trecarichi • S. Di Giambenedetto
•
Received: 15 October 2013 / Accepted: 31 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Etravirine is metabolized by three cytochrome P450 enzymes that are in turn induced by rifampin. Consequently, co-administration of etravirine and rifampin is not recommended. To date, however, no clinical studies exploring the drug–drug interaction of this combination have been conducted. Here we report two cases of off-label etravirine use concurrently with antitubercular treatment, dictated by the unavailability of other treatments. Plasma drug concentrations were monitored by regular measurements. Our results appear to confirm the increased metabolism of etravirine through the induction of cytochrome P450 enzymes, but the adequacy of drug levels in all of the measurements and subsequent virological suppression suggest that this drug interaction may not be clinically relevant. Keywords Drug interaction Rifamycin Non-nucleoside reverse transcriptase inhibitors Antiretroviral therapy Antitubercular therapy
Introduction According to the most recent guidelines, etravirine is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection only in antiretroviral treatmentexperienced adult patients, in combination with a boosted protease inhibitor and other antiretroviral drugs [1, 2]. Etravirine is metabolized by CYP3A4, CYP2C9 and CYP2C19 of the cytochrome P450 (CYP) family of enzymes [3]. These enzymes are induced by rifampin and, consequently, co-administration of etravirine and rifampin is not recommended [1, 2]. However, to date drug–drug interaction clinical studies have not been published. In this paper, we report the pharmacokinetic data and clinical outcomes of two HIV-infected patients affected by tuberculosis who were successfully treated with an etravirinecontaining combination antiretroviral therapy (cART) and rifampin-containing antitubercular therapy.
Case reports R. Gagliardini M. Fabbiani E. Visconti R. Cauda M. Colafigli E. M. Trecarichi S. Di Giambenedetto Institute of Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy M. Fabbiani (&) Istituto di Clinica delle Malattie Infettive, Universita` Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy e-mail: [email protected] S. Fortuna P. Navarra Institute of Pharmacology, Catholic University of Sacred Heart, Rome, Italy A. De Luca University Division of Infectious Diseases, University Hospital of Siena, Siena, Italy
The first case was that of a 28-year-old (approximate estimation) Caucasian woman with relevant weight loss (current weight 45 kg) and mood depression who was concomitantly diagnosed with cavitary pulmonary tuberculosis and HIV infection; HIV-RNA was 1,603,000 copies/mL and the CD4? cell count was 74/lL. Antitubercular therapy with rifampin (450 mg, once daily), ethambutol (400 mg, twice daily), pyrazinamide (1,000 mg, once daily) and isoniazid (replaced by moxifloxacin 400 mg, once daily, after 4 weeks because of isoniazid resistance) was immediately started, followed 1 week later with cART consisting of tenofovir/emtricitabine (300/100 mg, once daily) ? etravirine (200 mg, twice daily). Plasma HIV-
123
R. Gagliardini et al. Table 1 Plasma pharmacokinetics of etravirine during and after co-administration of rifampin Plasma pharmacokinetics
Reference valuesa
Patient 1
Patient 2
With rifampin Time (weeks) from initiation of ETR Ctrough (ng/mL) tmax (h)
184.7 (128.1) 4 (2–8)
Without rifampin
With rifampin
Without rifampin
2
32
36
42
13
25
570
139
466
1,006
50
603
4
2
3
4
3
4
Cmax (ng/mL)
451.3 (232.3)
1,060
499
1,323
2,285
206
1,192
AUC12 (ng h/mL)
3,713 (2,069)
8,855
3,395
9,610
19,890
1,303
9,628
ETR Etravirine, Ctrough minimum plasma drug concentration, tmax time to reach maximum plasma drug concentration (Cmax), AUC12 area under the time–concentration curve at 12 h a
Reference values, presented as the mean with standard deviation in parenthesis, except for tmax, which is presented as the mean with the range in parenthesis, are from a study in which etravirine was co-administered with boosted protease inhibitors, since etravirine is approved for clinical use only in this combination [6]
RNA showed a 4-log reduction after 2 months of treatment and became undetectable after 5 months, with substantial immunological recovery (CD4? 182/lL). Since two cerebral nodules were detected in frontal area by computed tomography (CT) scan, two lumbar punctures were performed 1 and 4 weeks after the initiation of cART. Both punctures revealed a slightly high protein content (52 and 43 mg/dL, respectively), while glycorrhachia and leucocytes were within the normal range. A direct smear, PCR and culture of cerebrospinal fluid (CSF) were negative for Mycobacterium tuberculosis; CSF HIV-RNA was 300 copies/mL in the first sample and \37 copies/mL in the second. The four-drug antitubercular regimen was continued for 7 months, followed by 2 months of combined rifampin ? moxifloxacin therapy. The second case was that of a 29-year-old (approximate estimation) Hispanic HIV-infected woman undergoing stable treatment with tenofovir/emtricitabine (300/100 mg, once daily) and darunavir/ritonavir (800/100 mg, once daily) who developed cavitary pulmonary tuberculosis. HIV-RNA was \37 copies/mL, CD4? cell count was 576/ lL and the baseline genotypic resistance test showed K101E mutation. Antitubercular treatment with rifampicin (600 mg, once daily), ethambutol (400 mg, three times a day), pyrazinamide (500 mg, three times a day) and isoniazid (300 mg, once daily) was started. Given the wellknown interactions between protease inhibitors (PIs) and rifampin and the low-level efavirenz resistance of the patient, darunavir/ritonavir was replaced with etravirine (200 mg, twice daily). After 2 months, clinical conditions improved, and the direct smear, PCR and sputum culture were negative for Mycobacterium tuberculosis. Antitubercular therapy was simplified to rifampin ? isoniazid and then stopped after 4 additional months. At the time of writing (7 and 3 months after discontinuation of antitubercular therapy, respectively), both patients are in good clinical condition, with HIV-RNA of \37 copies/mL and CD4? cell counts of 255 and
123
574 cells/lL, respectively. In the first patient, magnetic resonance imaging showed volume reduction of the cerebral nodules. In both patients, the plasma pharmacokinetic profile of etravirine [samples obtained at minimum concentration (Ctrough) and after 1, 2, 3, 4, 6, 12 h after drug intake] was assessed by a validated high-performance liquid chromatography–ultraviolet (HPLC–UV) assay (lower limit of quantification 50 ng/mL) [4] during and after rifampin treatment (Table 1). No other antiretroviral drug concentrations were assessed since relevant drug interactions between tenofovir, emtricitabine and the antitubercular treatment were not expected, and nucleos(t)ide reverse transcriptase inhibitors serum concentrations are not correlated to intracellular active drug concentrations [5]. A large increase in etravirine exposure was observed in both patients (?13,279 and ?8,325 ng h/mL, respectively) after discontinuation of rifampin. Etravirine measured in the two CSF samples obtained from the first patient was undetectable (\50 ng/mL) by the HPLC–UV assay.
Discussion Here we describe a successful outcome in two cases of offlabel etravirine use in association with rifampin-containing antitubercular therapy. The unusual choice of etravirine was dictated by the impossibility to administer efavirenz (for concomitant psychiatric disease in the first case and for the presence of resistance mutations to this drug in the second one). The concern of poor adherence (the first patient had depressive disorder, and the second one showed decreased motivation to continue cART) was a major determinant in these selected cases to prefer etravirine over raltegravir for its higher genetic barrier. Our data suggest that concomitant administration of etravirine and rifampin could be considered for the treatment of HIV-infected patients affected by tuberculosis.
Pharmacokinetics of etravirine in HIV-infected patients
Despite clinical success, the etravirine plasma levels in our patients were significantly reduced by rifampin co-administration, likely due to the increased metabolic clearance of etravirine through the induction of CYP isoenzymes by rifampin. However, the etravirine plasma concentrations in our patients were always well above its half maximal inhibitory concentration (IC50; 0.39–2.4 ng/mL), and HIVRNA suppression was also achieved/maintained in both patients. In our first patient, despite concomitant therapy with rifampin, etravirine levels were equal to or higher than those described in previous studies when etravirine was coadministered with or without boosted PIs [6, 7]; nevertheless, this patient had a low body weight. In our second patient, co-administration of etravirine and rifampin resulted in the area under the time–concentration curve (AUC) of etravirine being 364 % lower than the reference values [6]; following rifampin discontinuation, etravirine exposure was similar to that observed in patients treated with etravirine ? tenofovir and not receiving PIs [7]. Based on results from the GRACE study, Kakuda et al. [8] recently reported a high interindividual variability in etravirine pharmacokinetic parameters, with median (range) values for the AUC12 and Ctrough of etravirine being 4,183 (212–27,960) ng h/mL and 280 (4–2,211) ng/mL, respectively. In our patients, etravirine pharmacokinetic parameters when the patients were ‘‘off rifampin’’ fell within in the range observed in this study, despite being in the highest quartile. The low body weight (45 and 59 kg) and body mass index (19 and 22 kg/m2) could have determined this relatively higher exposure. One possible concern that could raise from GRACE study is the demonstrated association between low etravirine exposure and worse virological outcome. In the GRACE study, treatment-experienced adult patients with detectable HIV-RNA had the smallest changes in viral load and lowest virological response rates after 48 weeks from starting antiretroviral therapy when etravirine AUC12 or the Ctrough were in the lowest quartile (B2,712 ng h/mL and 160 ng/mL, respectively). In our patients, only one of these measurements fell into this lowest quartile. This occurred in our second patient who showed a low etravirine plasma concentration (Ctrough and AUC12) when rifampin was coadministered. However, this patient started an etravirinebased regimen when HIV-RNA undetectability had already been achieved. Theoretically, it could be possible that the levels of drugs required to maintain virological suppression in this setting may have been lower than those required in subjects with detectable HIV-RNA. Since in our patients virological suppression was constantly maintained and drug levels were kept above the reported IC50, this drug interaction might be considered not to be clinically relevant in patients without etravirine resistance mutations, but larger studies are required. Virological suppression in the
CSF was achieved despite low etravirine concentrations (below the detection limit of 50 ng/mL) in this compartment. In a previous study, a median CSF etravirine concentration of 7.24 ng/mL (range 3.59–17.9) was obtained [9]. Therefore, more sensitive methods are necessary to explore etravirine levels in CSF.
Conclusions These cases suggest a possible use of etravirine, even if offlabel, since it was not associated with a boosted PI in our two patients concomitantly treated with rifampin for tuberculosis, when other strategies are contraindicated or considered not feasible. However, virological and therapeutic drug monitoring is warranted since etravirine exposure is significantly reduced by the co-administration of rifampin. Acknowledgments
No specific funding was received for this study.
Conflict of interest MF received speakers’ honoraria from Merck Sharp & Dohme and Janssen-Cilag. PN received speakers’ honoraria from Boehringer Ingelheim, GlaxoSmithKline, Gilead and JanssenCilag. RC had been advisor for Gilead and Janssen-Cilag, received speakers’ honoraria from ViiV, Bristol-Myers Squibb, Merck Sharp and Dohme and Janssen-Cilag, and research support from ‘‘Fondazione Roma’’. MC has been a paid consultant for Merck Sharp & Dohme, Italy and was employed by Bristol-Myers-Squibb, Italy since May 10, 2010 to Feb 28 2011. ADL received speaker’s honoraria and fees for attending advisory boards from ViiV Healthcare, Gilead, Abbott Virology, Janssen-Tibotec, Siemens Diagnostics and Monogram Biosciences. SDG received speakers’ honoraria and support for travel meetings from Gilead, Bristol-Myers Squibb, Abbott, Boehringer Ingelheim, Janssen-Cilag, and GlaxoSmithKline. The other authors have nothing to declare.
References 1. European AIDS Clinical Society (EACS). Guidelines for the treatment of HIV infected adults in Europe. http://www.europea naidsclinicalsociety.org/images/stories/EACS-Pdf/EACSGuidelinesv6.1-English-Nov2012.pdf. Accessed 8 Oct 2013. 2. 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. http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandado lescentgl.pdf. Accessed 8 Oct 2013. 3. European Medicines Agency. Intelence 100 mg tablets: summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_Product_Information/human/000900/W C500034180.pdf. Accessed 8 Oct 2013. 4. Fabbiani M, Di Giambenedetto S, Bracciale L, et al. Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice. J Antimicrob Chemother 2009;64:109–17. 5. Bazzoli C, Jullien V, Le Tiec C, et al. Intracellular pharmacokinetics of antiretroviral drugs in HIV-infected patients, and their correlation with drug action. Clin Pharmacokinet. 2010;49(1):17–45.
123
R. Gagliardini et al. 6. Kakuda TN, Scho¨ller-Gyu¨re M, Workman C, et al. Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients. Antivir Ther. 2008;13:655–61. 7. Kakuda TN, Scholler-Gyure M, De Smedt G, et al. Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers. HIV Med. 2009;10:173–81.
123
8. Kakuda T, Sekar V, Vis P, et al. Pharmacokinetics and pharmacodynamics of darunavir and etravirine in HIV-1-infected, treatment-experienced patients in the Gender, Race, and Clinical Experience (GRACE) trial. AIDS Res Treat. 2012;2012:186987. doi: 10.1155/2012/186987 9. Tiraboschi JM, Niubo J, Vila A, et al. Etravirine concentrations in CSF in HIV-infected patients. J Antimicrob Chemother. 2012;67:1446–8.
CASE REPORT
Pharmacokinetics of etravirine in HIV-infected patients concomitantly treated with rifampin for tuberculosis R. Gagliardini • M. Fabbiani • S. Fortuna • E. Visconti P. Navarra • R. Cauda • M. Colafigli • A. De Luca • E. M. Trecarichi • S. Di Giambenedetto
•
Received: 15 October 2013 / Accepted: 31 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Etravirine is metabolized by three cytochrome P450 enzymes that are in turn induced by rifampin. Consequently, co-administration of etravirine and rifampin is not recommended. To date, however, no clinical studies exploring the drug–drug interaction of this combination have been conducted. Here we report two cases of off-label etravirine use concurrently with antitubercular treatment, dictated by the unavailability of other treatments. Plasma drug concentrations were monitored by regular measurements. Our results appear to confirm the increased metabolism of etravirine through the induction of cytochrome P450 enzymes, but the adequacy of drug levels in all of the measurements and subsequent virological suppression suggest that this drug interaction may not be clinically relevant. Keywords Drug interaction Rifamycin Non-nucleoside reverse transcriptase inhibitors Antiretroviral therapy Antitubercular therapy
Introduction According to the most recent guidelines, etravirine is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection only in antiretroviral treatmentexperienced adult patients, in combination with a boosted protease inhibitor and other antiretroviral drugs [1, 2]. Etravirine is metabolized by CYP3A4, CYP2C9 and CYP2C19 of the cytochrome P450 (CYP) family of enzymes [3]. These enzymes are induced by rifampin and, consequently, co-administration of etravirine and rifampin is not recommended [1, 2]. However, to date drug–drug interaction clinical studies have not been published. In this paper, we report the pharmacokinetic data and clinical outcomes of two HIV-infected patients affected by tuberculosis who were successfully treated with an etravirinecontaining combination antiretroviral therapy (cART) and rifampin-containing antitubercular therapy.
Case reports R. Gagliardini M. Fabbiani E. Visconti R. Cauda M. Colafigli E. M. Trecarichi S. Di Giambenedetto Institute of Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy M. Fabbiani (&) Istituto di Clinica delle Malattie Infettive, Universita` Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy e-mail: [email protected] S. Fortuna P. Navarra Institute of Pharmacology, Catholic University of Sacred Heart, Rome, Italy A. De Luca University Division of Infectious Diseases, University Hospital of Siena, Siena, Italy
The first case was that of a 28-year-old (approximate estimation) Caucasian woman with relevant weight loss (current weight 45 kg) and mood depression who was concomitantly diagnosed with cavitary pulmonary tuberculosis and HIV infection; HIV-RNA was 1,603,000 copies/mL and the CD4? cell count was 74/lL. Antitubercular therapy with rifampin (450 mg, once daily), ethambutol (400 mg, twice daily), pyrazinamide (1,000 mg, once daily) and isoniazid (replaced by moxifloxacin 400 mg, once daily, after 4 weeks because of isoniazid resistance) was immediately started, followed 1 week later with cART consisting of tenofovir/emtricitabine (300/100 mg, once daily) ? etravirine (200 mg, twice daily). Plasma HIV-
123
R. Gagliardini et al. Table 1 Plasma pharmacokinetics of etravirine during and after co-administration of rifampin Plasma pharmacokinetics
Reference valuesa
Patient 1
Patient 2
With rifampin Time (weeks) from initiation of ETR Ctrough (ng/mL) tmax (h)
184.7 (128.1) 4 (2–8)
Without rifampin
With rifampin
Without rifampin
2
32
36
42
13
25
570
139
466
1,006
50
603
4
2
3
4
3
4
Cmax (ng/mL)
451.3 (232.3)
1,060
499
1,323
2,285
206
1,192
AUC12 (ng h/mL)
3,713 (2,069)
8,855
3,395
9,610
19,890
1,303
9,628
ETR Etravirine, Ctrough minimum plasma drug concentration, tmax time to reach maximum plasma drug concentration (Cmax), AUC12 area under the time–concentration curve at 12 h a
Reference values, presented as the mean with standard deviation in parenthesis, except for tmax, which is presented as the mean with the range in parenthesis, are from a study in which etravirine was co-administered with boosted protease inhibitors, since etravirine is approved for clinical use only in this combination [6]
RNA showed a 4-log reduction after 2 months of treatment and became undetectable after 5 months, with substantial immunological recovery (CD4? 182/lL). Since two cerebral nodules were detected in frontal area by computed tomography (CT) scan, two lumbar punctures were performed 1 and 4 weeks after the initiation of cART. Both punctures revealed a slightly high protein content (52 and 43 mg/dL, respectively), while glycorrhachia and leucocytes were within the normal range. A direct smear, PCR and culture of cerebrospinal fluid (CSF) were negative for Mycobacterium tuberculosis; CSF HIV-RNA was 300 copies/mL in the first sample and \37 copies/mL in the second. The four-drug antitubercular regimen was continued for 7 months, followed by 2 months of combined rifampin ? moxifloxacin therapy. The second case was that of a 29-year-old (approximate estimation) Hispanic HIV-infected woman undergoing stable treatment with tenofovir/emtricitabine (300/100 mg, once daily) and darunavir/ritonavir (800/100 mg, once daily) who developed cavitary pulmonary tuberculosis. HIV-RNA was \37 copies/mL, CD4? cell count was 576/ lL and the baseline genotypic resistance test showed K101E mutation. Antitubercular treatment with rifampicin (600 mg, once daily), ethambutol (400 mg, three times a day), pyrazinamide (500 mg, three times a day) and isoniazid (300 mg, once daily) was started. Given the wellknown interactions between protease inhibitors (PIs) and rifampin and the low-level efavirenz resistance of the patient, darunavir/ritonavir was replaced with etravirine (200 mg, twice daily). After 2 months, clinical conditions improved, and the direct smear, PCR and sputum culture were negative for Mycobacterium tuberculosis. Antitubercular therapy was simplified to rifampin ? isoniazid and then stopped after 4 additional months. At the time of writing (7 and 3 months after discontinuation of antitubercular therapy, respectively), both patients are in good clinical condition, with HIV-RNA of \37 copies/mL and CD4? cell counts of 255 and
123
574 cells/lL, respectively. In the first patient, magnetic resonance imaging showed volume reduction of the cerebral nodules. In both patients, the plasma pharmacokinetic profile of etravirine [samples obtained at minimum concentration (Ctrough) and after 1, 2, 3, 4, 6, 12 h after drug intake] was assessed by a validated high-performance liquid chromatography–ultraviolet (HPLC–UV) assay (lower limit of quantification 50 ng/mL) [4] during and after rifampin treatment (Table 1). No other antiretroviral drug concentrations were assessed since relevant drug interactions between tenofovir, emtricitabine and the antitubercular treatment were not expected, and nucleos(t)ide reverse transcriptase inhibitors serum concentrations are not correlated to intracellular active drug concentrations [5]. A large increase in etravirine exposure was observed in both patients (?13,279 and ?8,325 ng h/mL, respectively) after discontinuation of rifampin. Etravirine measured in the two CSF samples obtained from the first patient was undetectable (\50 ng/mL) by the HPLC–UV assay.
Discussion Here we describe a successful outcome in two cases of offlabel etravirine use in association with rifampin-containing antitubercular therapy. The unusual choice of etravirine was dictated by the impossibility to administer efavirenz (for concomitant psychiatric disease in the first case and for the presence of resistance mutations to this drug in the second one). The concern of poor adherence (the first patient had depressive disorder, and the second one showed decreased motivation to continue cART) was a major determinant in these selected cases to prefer etravirine over raltegravir for its higher genetic barrier. Our data suggest that concomitant administration of etravirine and rifampin could be considered for the treatment of HIV-infected patients affected by tuberculosis.
Pharmacokinetics of etravirine in HIV-infected patients
Despite clinical success, the etravirine plasma levels in our patients were significantly reduced by rifampin co-administration, likely due to the increased metabolic clearance of etravirine through the induction of CYP isoenzymes by rifampin. However, the etravirine plasma concentrations in our patients were always well above its half maximal inhibitory concentration (IC50; 0.39–2.4 ng/mL), and HIVRNA suppression was also achieved/maintained in both patients. In our first patient, despite concomitant therapy with rifampin, etravirine levels were equal to or higher than those described in previous studies when etravirine was coadministered with or without boosted PIs [6, 7]; nevertheless, this patient had a low body weight. In our second patient, co-administration of etravirine and rifampin resulted in the area under the time–concentration curve (AUC) of etravirine being 364 % lower than the reference values [6]; following rifampin discontinuation, etravirine exposure was similar to that observed in patients treated with etravirine ? tenofovir and not receiving PIs [7]. Based on results from the GRACE study, Kakuda et al. [8] recently reported a high interindividual variability in etravirine pharmacokinetic parameters, with median (range) values for the AUC12 and Ctrough of etravirine being 4,183 (212–27,960) ng h/mL and 280 (4–2,211) ng/mL, respectively. In our patients, etravirine pharmacokinetic parameters when the patients were ‘‘off rifampin’’ fell within in the range observed in this study, despite being in the highest quartile. The low body weight (45 and 59 kg) and body mass index (19 and 22 kg/m2) could have determined this relatively higher exposure. One possible concern that could raise from GRACE study is the demonstrated association between low etravirine exposure and worse virological outcome. In the GRACE study, treatment-experienced adult patients with detectable HIV-RNA had the smallest changes in viral load and lowest virological response rates after 48 weeks from starting antiretroviral therapy when etravirine AUC12 or the Ctrough were in the lowest quartile (B2,712 ng h/mL and 160 ng/mL, respectively). In our patients, only one of these measurements fell into this lowest quartile. This occurred in our second patient who showed a low etravirine plasma concentration (Ctrough and AUC12) when rifampin was coadministered. However, this patient started an etravirinebased regimen when HIV-RNA undetectability had already been achieved. Theoretically, it could be possible that the levels of drugs required to maintain virological suppression in this setting may have been lower than those required in subjects with detectable HIV-RNA. Since in our patients virological suppression was constantly maintained and drug levels were kept above the reported IC50, this drug interaction might be considered not to be clinically relevant in patients without etravirine resistance mutations, but larger studies are required. Virological suppression in the
CSF was achieved despite low etravirine concentrations (below the detection limit of 50 ng/mL) in this compartment. In a previous study, a median CSF etravirine concentration of 7.24 ng/mL (range 3.59–17.9) was obtained [9]. Therefore, more sensitive methods are necessary to explore etravirine levels in CSF.
Conclusions These cases suggest a possible use of etravirine, even if offlabel, since it was not associated with a boosted PI in our two patients concomitantly treated with rifampin for tuberculosis, when other strategies are contraindicated or considered not feasible. However, virological and therapeutic drug monitoring is warranted since etravirine exposure is significantly reduced by the co-administration of rifampin. Acknowledgments
No specific funding was received for this study.
Conflict of interest MF received speakers’ honoraria from Merck Sharp & Dohme and Janssen-Cilag. PN received speakers’ honoraria from Boehringer Ingelheim, GlaxoSmithKline, Gilead and JanssenCilag. RC had been advisor for Gilead and Janssen-Cilag, received speakers’ honoraria from ViiV, Bristol-Myers Squibb, Merck Sharp and Dohme and Janssen-Cilag, and research support from ‘‘Fondazione Roma’’. MC has been a paid consultant for Merck Sharp & Dohme, Italy and was employed by Bristol-Myers-Squibb, Italy since May 10, 2010 to Feb 28 2011. ADL received speaker’s honoraria and fees for attending advisory boards from ViiV Healthcare, Gilead, Abbott Virology, Janssen-Tibotec, Siemens Diagnostics and Monogram Biosciences. SDG received speakers’ honoraria and support for travel meetings from Gilead, Bristol-Myers Squibb, Abbott, Boehringer Ingelheim, Janssen-Cilag, and GlaxoSmithKline. The other authors have nothing to declare.
References 1. European AIDS Clinical Society (EACS). Guidelines for the treatment of HIV infected adults in Europe. http://www.europea naidsclinicalsociety.org/images/stories/EACS-Pdf/EACSGuidelinesv6.1-English-Nov2012.pdf. Accessed 8 Oct 2013. 2. 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. http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandado lescentgl.pdf. Accessed 8 Oct 2013. 3. European Medicines Agency. Intelence 100 mg tablets: summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_Product_Information/human/000900/W C500034180.pdf. Accessed 8 Oct 2013. 4. Fabbiani M, Di Giambenedetto S, Bracciale L, et al. Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice. J Antimicrob Chemother 2009;64:109–17. 5. Bazzoli C, Jullien V, Le Tiec C, et al. Intracellular pharmacokinetics of antiretroviral drugs in HIV-infected patients, and their correlation with drug action. Clin Pharmacokinet. 2010;49(1):17–45.
123
R. Gagliardini et al. 6. Kakuda TN, Scho¨ller-Gyu¨re M, Workman C, et al. Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients. Antivir Ther. 2008;13:655–61. 7. Kakuda TN, Scholler-Gyure M, De Smedt G, et al. Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers. HIV Med. 2009;10:173–81.
123
8. Kakuda T, Sekar V, Vis P, et al. Pharmacokinetics and pharmacodynamics of darunavir and etravirine in HIV-1-infected, treatment-experienced patients in the Gender, Race, and Clinical Experience (GRACE) trial. AIDS Res Treat. 2012;2012:186987. doi: 10.1155/2012/186987 9. Tiraboschi JM, Niubo J, Vila A, et al. Etravirine concentrations in CSF in HIV-infected patients. J Antimicrob Chemother. 2012;67:1446–8.
