Correspondence AIDS 2014, 28:1993–1997
No pharmacokinetic interaction between raltegravir and amlodipine: importance for co-prescribing in ageing HIV-infected individuals HIV-infected patients require lifelong combination antiretroviral therapy and are more likely to be affected by comorbidities during prolonged survival, in particular hypertension and atherosclerosis as causes of cardiovascular disease [1]; these conditions also require continuous pharmacotherapy. Thus, the management of older HIVinfected patients is challenging and complicated by the high potential for drug-drug interactions (DDIs) between antiretrovirals and cardiovascular drugs [2,3]. Hence, it is important to identify favourable combinations, characterized by the absence of DDI, in order to safely manage the concurrent long-term treatment of both conditions. Raltegravir is an integrase inhibitor approved for the treatment of HIV infection at 400 mg twice daily in combination with two nucleoside analogues. Raltegravir is not a substrate of cytochrome P450 (CYP450); it is primarily metabolized to raltegravir glucuronide, by uridine diphosphoglucuronosyl transferase (UGT) 1A1 [4]. Calcium channel blockers (amlodipine in particular) are the preferred first-line antihypertensives for most people (from both efficacy and a cost point of view) [5]. However, they are substrates of CYP450 and plasma concentrations have been shown to increase, causing toxicity, when co-administered with ritonavir boosted protease inhibitors [6]. There are no data on the co-administration of integrase inhibitors and amlodipine, and we therefore evaluated the bidirectional pharmacokinetic interaction between raltegravir and amlodipine.
plasma concentrations were analyzed by a validated ultraperformance liquid chromatography-MS/MS method, modified from Zhou et al. [8] Pharmacokinetic parameters were determined by noncompartmental methods (WinNonlin Phoenix, version 6.1; Pharsight Corp, Mountain View, California, USA). These were the concentrations measured 12 and 24 h postdose (C12h, C24h) for raltegravir and amlodipine, respectively; the maximum concentration (Cmax); and the area under the curve over 12 and 24 h (AUC12h, AUC24h) for raltegravir and amlodipine, respectively. Within-participant changes in the assessed pharmacokinetic parameters (drug alone versus drug combination) were evaluated by calculating geometric mean ratios and 90% confidence intervals (CIs; these were determined using logarithms of the individual geometric mean values and expressed as linear values). Seventeen (13 female) subjects completed the study. Median (range) age and BMI were 34 (21–51) and 17.4 (13.0–22.6) kg/m2, respectively. The study drugs were well tolerated and no serious adverse events were reported. Concentration-time curves for raltegravir (without and with amlodipine) and amlodipine (with and without raltegravir) are illustrated in Fig. 1.
Following written consent and screening procedures, we enrolled HIV-negative male and female volunteers in a phase I, open-label, cross-over pharmacokinetic study (approved by Westminster Research Ethics Committee and UK Regulatory Authorities; Eudra number 2012005400-18). Participants were randomized to receive either raltegravir 400 mg twice daily (7 days), followed by raltegravir 400 mg twice daily plus amlodipine 5 mg once daily (7 days), followed by amlodipine 5 mg once daily alone (7 days), or the same treatments in the opposite order, in the fasted state (at least 8 h) with 240 ml of water.
Geometric mean (95% CI) raltegravir parameters, without and with amlodipine, respectively were: for Cmax, 1178 (966–2318) and 1866 (1779–4511) ng/ml; for C12h, 48 (35–95) and 37 (30–67) ng/ml; and for AUC0–12h, 4600 (3888–7652) and 6410 (5649–12138) ng/h/ml. Geometric mean ratios and 90% CI of raltegravir (with amlodipine versus alone) were 1.58 (0.84–3.09) for the Cmax, 0.78 (0.57–1.04) for the C12h, and 1.39 (0.87–2.29) for the AUC0–12h. Geometric mean (95% CI) amlodipine parameters, without and with amlodipine, respectively, were: for Cmax, 8.47 (7.58–10.0) and 8.49 (7.65–9.94) ng/ml; for C24h, 4.91 (4.23–6.36) and 4.55 (4.11–5.34) ng/ml; and for AUC0–24h, 166.0 (146.3–202.9) and (165.9 (148.7– 195.8) ng/h/ml. Geometric mean ratios and 90% CI of amlodipine (with raltegravir versus alone) were 1.00 (0.90–1.22) for the Cmax, 0.93 (0.80–1.08) for the C24h, and 0.99 (0.89–1.12) for the AUC0–24h.
Intensive pharmacokinetic sampling and safety laboratory analysis were performed at the end of each phase (days 7, 14 and 21). Raltegravir plasma concentrations were analyzed by a validated liquid chromatography–mass spectrometry (LC-MS/MS) method [7]. Amlodipine
Importantly, raltegravir did not alter amlodipine plasma exposure and amlodipine did not have a significant effect on raltegravir plasma concentrations, suggesting that co-administration of the two drugs is well tolerated in the clinical setting.
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
1993
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
AIDS
Raltegravir (ng/mL)
(a)
2014, Vol 28 No 13
are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Limited. Funding support was also provided by the St Stephen’s AIDS Trust.
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Transparency declarations: G.J.S. received travel grants from Janssen, Boehringer Ingelheim and Gilead; A.J. received travel grants from Janssen and consulting fees from Merck Sharp & Dohme; S.B., G.D.P., S.K., D.B., G.M., M.B. received travel and research grants from and have been advisers for Janssen, Roche, Pfizer, ViiV, Bristol-Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, AbbieVie, and Gilead. This work was partially presented at the Third Joint Conference of the British HIV Association (BHIVA) with the British Association for Sexual Health and HIV (BASHH), April 2014, Liverpool, UK.
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Conflicts of interest There are no conflicts of interest for the remaining authors. 1 0
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Fig. 1. Plasma pharmacokinetic profiles of raltegravir and amlodipine. (a) Raltegravir concentrations in the presence (squares) and in the absence (diamonds) of amlodipine; (b) amlodipine concentrations in the presence (squares) and in the absence (diamonds) of raltegravir.
The management of HIV infection continues to evolve and DDIs are becoming increasingly complex. Although DDI databases (e.g. www.hiv-druginteractions.org) are available to assist clinical care providers with the management of these interactions, clinicians should also recognize drugs with the lowest potential for interactions. As HIV-infected patients survive to older ages, DDIs arising from the management of other health problems will be more common in the future. In conclusion, our study demonstrates the lack of a significant DDI between raltegravir and amlodipine and increases the knowledge on drug combinations that may simplify the complex management of HIV-infected individuals receiving polypharmacy.
Acknowledgements The authors would like to thank the volunteers who took part in the study and the St Stephen’s AIDS Trust Research Team for their hard work. This study was supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Limited. The opinions expressed in this article
Gurmit J. Singha, Akil Jacksona, Antonio D’Avoliob, Laura Elsec, Amedeo De Nicolo`b, Stefano Bonorab, Giovanni Di Perrib, Saye Khooc, David Backc, Graeme Moylea and Marta Boffitoa, aSt. Stephen’s Centre, Chelsea and Westminster Hospital, London, UK, b Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Turin, Italy, and cDepartment of Molecular & Clinical Pharmacology, Liverpool Bioanalytical Facility, University of Liverpool, Liverpool, UK. Correspondence to Dr. Marta Boffito, St. Stephen’s Centre – Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel: +44 (0)20 33156506; fax: +44 (0)20 33155628; e-mail: [email protected] Received: 1 May 2014; revised: 16 May 2014; accepted: 19 May 2014.
References 1. Data Collection on Adverse Events of Anti-HIV Drugs D:A:D study. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003. 2. Tseng A, Foisy M. Important drug-drug interactions in HIVinfected persons on antiretroviral therapy: an update on new interactions between HIV and non-HIV drugs. Curr Infect Dis Rep 2012; 14:; 67–82–82. 3. Marzolini C, Back D, Weber R, Furrer H, Cavassini M, Calmy A, et al. Ageing with HIV: medication use and risk for potential drug-drug interactions. J Antimicrob Chemother 2011; 66:2107– 2111. 4. Merck Sharp Dohme Limited. Raltegravir (Isentress) Summary of Product Charateristics. electronic Medicines Compendium (eMC). http://www.medicines.org.uk/emc/medicine/20484#INTERACTIONS [Accessed 15 April 2014]. 5. Hypertension - Clinical management of primary hypertension in adults. National Institute for Health and Clinical Excellence. 2011. http://www.nice.org.uk/nicemedia/live/13561/56008/ 56008.pdf [Accessed 15 April 2014].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence 6. Glesby MJ, Aberg JA, Kendall MA, Fichtenbaum CJ, Hafner R, Hall S, et al. Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers. Clin Pharmacol Ther 2005; 78:143–153. 7. Else L, Watson V, Tjia J, Hughes A, Siccardi M, Khoo S, et al. Validation of a rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for the simultaneous determination of existing and new antiretroviral compounds. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878:1455–1465.
1995
8. Zhou Y, Li J, He X, Jia M, Liu M, Li H, et al. Development and validation of a liquid chromatography-tandem mass spectrometry method for simultaneous determination of amlodipine, atorvastatin and its metabolites ortho-hydroxy atorvastatin and para-hydroxy atorvastatin in human plasma and its application in a bioequivalence study. J Pharm Biomed Anal 2013; 83:101– 107.
DOI:10.1097/QAD.0000000000000356
Should we not pay attention to what women tell us when they vote with their feet? We note with fascination that the authors of an article finding higher loss to follow up (LTF) in women presented with the so-called and misnamed ‘Option’ Bþ have concluded that ‘Decreasing LTF will improve the effectiveness of the Option Bþ approach’ [1]. Could we not also consider the explanation that women may be acting entirely rationally when not returning to a health facility that does not prioritize their sexual and reproductive rights? Women offered ‘Option Bþ’ are not being treated as ends in themselves, they are being used as a means to another end. As if receiving a diagnosis of HIV during pregnancy was not enough of a blow, women were not given counselling as to their options nor offered monitoring and treatment at a time that would maximize their long-term health and a securer future. Women might have more pressing concerns such as their immediate health and well being, stigmatization, genderbased violence [2] and everyday life to cope with. As ‘Option’ Bþ was foisted on women on the very same day as receiving their diagnosis with no time to gather their thoughts, what more could possibly improve LTF short of coercion? Thus, on the same findings, the authors might have concluded that decreasing the Option Bþ approach will improve the loss to follow up and effectiveness of antiretrovirals when they are required. Rather than concluding that ‘Tailored interventions, like community or family-based models of care could improve its [Option Bþ] effectiveness’, we believe that the authors might have considered that tailored interventions, such as highquality rational care based on the individual needs of the woman and her baby, could improve its (antiretroviral, ARV) effectiveness. The latter approach might be as empathic and effective as well as respecting human rights. We recommend a reappraisal of Option Bþ.
Acknowledgements AW is Founding Director of the Salamander Trust and Co-Founder and Co-Chair of the Sophia Forum, charities working for women living with HIV globally and in the UK. SB is a trustee of the Sophia Forum. Both are involved in a global community consultation for the WHO update of its 2006 Sexual and Reproductive Health and Human Rights Guidelines for women living with HIV.
Conflicts of interest There are no conflicts of interest. Susan Bewleya and Alice Welbournb, aWomen’s Health Academic Centre, King’s College London, London, UK, and bSalamander Trust, London, UK. Correspondence to Susan Bewley, MD, King’s College London, London SE1 7NH, UK. E-mail: [email protected] Received: 12 April 2014; revised: 27 May 2014; accepted: 29 May 2014.
References 1. Tenthani L, Haas AD, Tweya H, Jahn A, van Oosterhout J, Chimbwandira F, et al. Retention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women (‘Option BR’) in Malawi. AIDS 2014; 28:589–598. 2. Salamander Trust and Members of the Coalition of Women Living with HIV and AIDS in Malawi. Seeking safety: Stepping Stones in Malawi. https://vimeo.com/69251113 [Accessed 12 April 2014].
DOI:10.1097/QAD.0000000000000370
Skeletal muscle toxicity associated with emtricitabine/rilpivirine/tenofovir fixed-dose combination: a case report French, European and US guidelines recommend earlier initiation of combined anti-retroviral treatments (cART) [1–3]. Currently, cARTs are overall associated with fewer adverse events. Fixed dose combinations (FDCs) and single treatment regimen are more and more frequently used in HIV-infected patients because they are easier to take and thus considered to improve adherence.
However, hindsight is still needed to fully assess the rare adverse events. We describe here the first case of skeletal muscle toxicity associated with rilpivirine (RPV). A 63-year-old man was consulted in June 2013 for subacute weight gain, fatigue and muscular pain. He had an A1 stage past medical history of HIV infection since
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1996
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2014, Vol 28 No 13
1985, with good immunologic profile and an undetectable plasma HIV-1 RNA for 12 years. His cART history began with zidovudine/lamivudine/abacavir FDC, continued with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF)/efavirenz (EFV) FDC during 12 years recently changed from January 2013 for FTC/TDF/RPV FDC due to lipid abnormalities. Apart from HIV, he had a stable history of heart angina. He also presented HCV infection successfully treated in 2011 with sustained viral response. He was a semi-professional swimmer and still recently in excellent physical condition. Since the last switch to TDF/FTC/RPV FDC, he rapidly complained of change in his body shape, a gain of 8 kg of abdominal fat, myalgia at mild efforts and proximal muscular loss.
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Physical examination showed dual lipodystrophia with android obesity and amyotrophy of the proximal muscles. Creatine phosphokinase, aldolase and aspartate aminotransferase were normal. An abdominal computed tomographic scan showed inter-visceral fat accumulation. A muscular biopsy was performed and diagnosed a toxic myopathy with mitochondrial proliferations and cyclooxygenase (Cox)-negative fibres. There were no lipid inclusions, no vasculitis and no infiltrates. Tumour necrosis factor-alpha (TNF)-alpha and leptin circulating levels increased whereas adiponectin decreased during the acute cytopathy event (2.4, 5.6 and 4.2 pg/ml; 4.4, 5.7 and 4.5 ng/ml, respectively, before and during the cytopathy event). RPV, tenofovir and FTC concentrations 12 h after the last drug intake were at 377, 180, and 429 ng/ml, respectively. All were above the upper limit of acceptable concentrations. Consequently, RPV was discontinued in this patient and the EFV reinitiated with the same TDF/FTC backbone. Two months after the switch, the patient was doing well, no more complaining of fatigue and muscular pain; he has lost 6 kg in less than 2 weeks after switching. Circulating levels of TNF-alpha, leptin and adiponectin went back to normal values after the RPV switch (5.8, 3.6 and 5.3 mg/ml). Six months after the switch, he has now returned to his original weight (a total loss of 10 kg) and was able to practice swimming as well. Figure 1 presents disease slides with succinate dehydrogenase and Cox activities. RPV is a recently approved second-generation nonnucleoside reverse transcriptase inhibitor, marketed in coformulation with TDF and FTC in fixed-dose combination. It has demonstrated its noninferiority when compared with EFV as a first-line therapy and is an attractive option for switching therapy. Since the first clinical trials in 2008 and its approval in 2011, RPV has shown an excellent safety profile, compared in particular to EFV. The latest follow-up at 96 weeks has shown few neurologic or psychiatric symptoms, dermatologic abnormalities and mild changes in total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride
Fig. 1. Histo-Enzymology on frozen section of deltoid muscle fragment. (a) Succinate dehydrogenase activity (arrow show fiber with mitochondrial proliferation). (b) Cyclooxygenase (Cox) activity (arrow show fiber with no Cox activity).
[4,5]. A case report of severe induced hepatitis on RPV has been published [6,7]. We describe here, to our knowledge, the first case of muscle toxicity associated with a FDC containing RPV. Although we have no clear causal relationship, the accountability of RPV is strong because it was the only changed drug during this period, and its discontinuation has led to an improvement of the symptoms. It was not ruled out whether this adverse event was the result of an excessive concentration or an intrinsic property of RPV. Both EFV and RPV plasma concentrations were above the respective toxicity cut-offs (4000 and 300 ng/ml, respectively). For EFV, such high concentrations might be explained by Cytochrome P450 2B6 genetic polymorphism. For RPV, the recent HCV liver disease (despite the successful treatment in 2011 and any significant fibrosis) might be an explanation of the higher plasma exposure observed. To conclude, even with new FDC regimens considered to be much better tolerated than previous ART regimens, data regarding follow-up of the new drugs are still scarce. This case report describes the first case of skeletal muscle toxicity. Our data suggest that it could be dose-dependent. Plasma concentrations must be of
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Correspondence
interest when adverse events are suspected to rule out toxicity.
Correspondence to Liem Binh Luong Nguyen, Infectious Diseases Department, Bichat Claude Bernard Hospital, 46 rue Huchard, 75018 Paris. E-mail: [email protected]
Acknowledgements
Received: 27 May 2014; revised: 13 June 2014; accepted: 23 June 2014.
Conflicts of interest S.H. has received travel grants from BMS and MSD. G.P. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers-Squibb, Gilead Sciences, Janssen, Merck, ViiV Healthcare and Splicos. Y.Y. is a board member and reports receiving consultancy honoria from Abbott, BMS, Gilead, MSD, Roche, Tibotec and ViiV Healthcare; he also reports receiving honoraria for development of educational presentations from Abbott, BMS, Gilead, Tibotec and ViiV Healthcare. F.X.L. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers-Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. Liem Binh Luong Nguyena, Stanislas Harent a, Gilles Peytavinb,c, Benoit Visseauxb,d, Jean P. Bastarde, Odile Dubourgf, Sylvie Larivena, Patrick Yenia, Yazdan Yazdanpanaha,b and Francois X. Lescurea,b, a Infectious Diseases Department, Bichat Claude Bernard Hospital, bIAME, UMR 1137, INSERM, Universite´ Paris Diderot, cUF 301 Pharmaco-Toxicology Department, Bichat Claude Bernard Hospital, dLaboratoire de Virologie, Bichat Hospital, eBiochemistry Department, Tenon Hospital, and fNeuropathology Department, Pitie´-Salpetrie`re Hospital, AP-HP, Paris, France.
1997
References 1. Philippe M. Prise en charge me´dicale des personnes vivant avec le VIH [Medical Management of people living with AIDS, Documentation Franc¸aise]. La documentation franc¸aise 2013. 2. Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the international antiviral society – USA panel. JAMA 2012; 308:387–402. 3. EACS. Guidelines for treatment of HIV-infected adults in Europe. 2013. http://eacsociety.org/Guidelines.aspx 4. Cohen CJ, Molina J-M, Cahn P, Clotet B, Fourie J, Grinsztejn B, et al., THRIVE Study Group. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr 2012; 60:33–42. 5. Cohen CJ, Molina J-M, Cassetti I, Chetchotisakd P, Lazzarin A, Orkin C, et al., ECHO, THRIVE study groups. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS 2013; 27:939–950. 6. Ahmed Y, Siddiqui W, Enoch CB, Albrecht H, Bookstaver PB. Rare case of rilpivirine-induced severe allergic hepatitis. J Antimicrob Chemother 2013; 68:484–486. 7. Casado JL. Liver toxicity in HIV-infected patients receiving novel second-generation nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine. AIDS Rev 2013; 15:139–145.
DOI:10.1097/QAD.0000000000000387
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
No pharmacokinetic interaction between raltegravir and amlodipine: importance for co-prescribing in ageing HIV-infected individuals HIV-infected patients require lifelong combination antiretroviral therapy and are more likely to be affected by comorbidities during prolonged survival, in particular hypertension and atherosclerosis as causes of cardiovascular disease [1]; these conditions also require continuous pharmacotherapy. Thus, the management of older HIVinfected patients is challenging and complicated by the high potential for drug-drug interactions (DDIs) between antiretrovirals and cardiovascular drugs [2,3]. Hence, it is important to identify favourable combinations, characterized by the absence of DDI, in order to safely manage the concurrent long-term treatment of both conditions. Raltegravir is an integrase inhibitor approved for the treatment of HIV infection at 400 mg twice daily in combination with two nucleoside analogues. Raltegravir is not a substrate of cytochrome P450 (CYP450); it is primarily metabolized to raltegravir glucuronide, by uridine diphosphoglucuronosyl transferase (UGT) 1A1 [4]. Calcium channel blockers (amlodipine in particular) are the preferred first-line antihypertensives for most people (from both efficacy and a cost point of view) [5]. However, they are substrates of CYP450 and plasma concentrations have been shown to increase, causing toxicity, when co-administered with ritonavir boosted protease inhibitors [6]. There are no data on the co-administration of integrase inhibitors and amlodipine, and we therefore evaluated the bidirectional pharmacokinetic interaction between raltegravir and amlodipine.
plasma concentrations were analyzed by a validated ultraperformance liquid chromatography-MS/MS method, modified from Zhou et al. [8] Pharmacokinetic parameters were determined by noncompartmental methods (WinNonlin Phoenix, version 6.1; Pharsight Corp, Mountain View, California, USA). These were the concentrations measured 12 and 24 h postdose (C12h, C24h) for raltegravir and amlodipine, respectively; the maximum concentration (Cmax); and the area under the curve over 12 and 24 h (AUC12h, AUC24h) for raltegravir and amlodipine, respectively. Within-participant changes in the assessed pharmacokinetic parameters (drug alone versus drug combination) were evaluated by calculating geometric mean ratios and 90% confidence intervals (CIs; these were determined using logarithms of the individual geometric mean values and expressed as linear values). Seventeen (13 female) subjects completed the study. Median (range) age and BMI were 34 (21–51) and 17.4 (13.0–22.6) kg/m2, respectively. The study drugs were well tolerated and no serious adverse events were reported. Concentration-time curves for raltegravir (without and with amlodipine) and amlodipine (with and without raltegravir) are illustrated in Fig. 1.
Following written consent and screening procedures, we enrolled HIV-negative male and female volunteers in a phase I, open-label, cross-over pharmacokinetic study (approved by Westminster Research Ethics Committee and UK Regulatory Authorities; Eudra number 2012005400-18). Participants were randomized to receive either raltegravir 400 mg twice daily (7 days), followed by raltegravir 400 mg twice daily plus amlodipine 5 mg once daily (7 days), followed by amlodipine 5 mg once daily alone (7 days), or the same treatments in the opposite order, in the fasted state (at least 8 h) with 240 ml of water.
Geometric mean (95% CI) raltegravir parameters, without and with amlodipine, respectively were: for Cmax, 1178 (966–2318) and 1866 (1779–4511) ng/ml; for C12h, 48 (35–95) and 37 (30–67) ng/ml; and for AUC0–12h, 4600 (3888–7652) and 6410 (5649–12138) ng/h/ml. Geometric mean ratios and 90% CI of raltegravir (with amlodipine versus alone) were 1.58 (0.84–3.09) for the Cmax, 0.78 (0.57–1.04) for the C12h, and 1.39 (0.87–2.29) for the AUC0–12h. Geometric mean (95% CI) amlodipine parameters, without and with amlodipine, respectively, were: for Cmax, 8.47 (7.58–10.0) and 8.49 (7.65–9.94) ng/ml; for C24h, 4.91 (4.23–6.36) and 4.55 (4.11–5.34) ng/ml; and for AUC0–24h, 166.0 (146.3–202.9) and (165.9 (148.7– 195.8) ng/h/ml. Geometric mean ratios and 90% CI of amlodipine (with raltegravir versus alone) were 1.00 (0.90–1.22) for the Cmax, 0.93 (0.80–1.08) for the C24h, and 0.99 (0.89–1.12) for the AUC0–24h.
Intensive pharmacokinetic sampling and safety laboratory analysis were performed at the end of each phase (days 7, 14 and 21). Raltegravir plasma concentrations were analyzed by a validated liquid chromatography–mass spectrometry (LC-MS/MS) method [7]. Amlodipine
Importantly, raltegravir did not alter amlodipine plasma exposure and amlodipine did not have a significant effect on raltegravir plasma concentrations, suggesting that co-administration of the two drugs is well tolerated in the clinical setting.
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
1993
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
AIDS
Raltegravir (ng/mL)
(a)
2014, Vol 28 No 13
are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Limited. Funding support was also provided by the St Stephen’s AIDS Trust.
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Transparency declarations: G.J.S. received travel grants from Janssen, Boehringer Ingelheim and Gilead; A.J. received travel grants from Janssen and consulting fees from Merck Sharp & Dohme; S.B., G.D.P., S.K., D.B., G.M., M.B. received travel and research grants from and have been advisers for Janssen, Roche, Pfizer, ViiV, Bristol-Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, AbbieVie, and Gilead. This work was partially presented at the Third Joint Conference of the British HIV Association (BHIVA) with the British Association for Sexual Health and HIV (BASHH), April 2014, Liverpool, UK.
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Fig. 1. Plasma pharmacokinetic profiles of raltegravir and amlodipine. (a) Raltegravir concentrations in the presence (squares) and in the absence (diamonds) of amlodipine; (b) amlodipine concentrations in the presence (squares) and in the absence (diamonds) of raltegravir.
The management of HIV infection continues to evolve and DDIs are becoming increasingly complex. Although DDI databases (e.g. www.hiv-druginteractions.org) are available to assist clinical care providers with the management of these interactions, clinicians should also recognize drugs with the lowest potential for interactions. As HIV-infected patients survive to older ages, DDIs arising from the management of other health problems will be more common in the future. In conclusion, our study demonstrates the lack of a significant DDI between raltegravir and amlodipine and increases the knowledge on drug combinations that may simplify the complex management of HIV-infected individuals receiving polypharmacy.
Acknowledgements The authors would like to thank the volunteers who took part in the study and the St Stephen’s AIDS Trust Research Team for their hard work. This study was supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Limited. The opinions expressed in this article
Gurmit J. Singha, Akil Jacksona, Antonio D’Avoliob, Laura Elsec, Amedeo De Nicolo`b, Stefano Bonorab, Giovanni Di Perrib, Saye Khooc, David Backc, Graeme Moylea and Marta Boffitoa, aSt. Stephen’s Centre, Chelsea and Westminster Hospital, London, UK, b Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Turin, Italy, and cDepartment of Molecular & Clinical Pharmacology, Liverpool Bioanalytical Facility, University of Liverpool, Liverpool, UK. Correspondence to Dr. Marta Boffito, St. Stephen’s Centre – Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel: +44 (0)20 33156506; fax: +44 (0)20 33155628; e-mail: [email protected] Received: 1 May 2014; revised: 16 May 2014; accepted: 19 May 2014.
References 1. Data Collection on Adverse Events of Anti-HIV Drugs D:A:D study. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003. 2. Tseng A, Foisy M. Important drug-drug interactions in HIVinfected persons on antiretroviral therapy: an update on new interactions between HIV and non-HIV drugs. Curr Infect Dis Rep 2012; 14:; 67–82–82. 3. Marzolini C, Back D, Weber R, Furrer H, Cavassini M, Calmy A, et al. Ageing with HIV: medication use and risk for potential drug-drug interactions. J Antimicrob Chemother 2011; 66:2107– 2111. 4. Merck Sharp Dohme Limited. Raltegravir (Isentress) Summary of Product Charateristics. electronic Medicines Compendium (eMC). http://www.medicines.org.uk/emc/medicine/20484#INTERACTIONS [Accessed 15 April 2014]. 5. Hypertension - Clinical management of primary hypertension in adults. National Institute for Health and Clinical Excellence. 2011. http://www.nice.org.uk/nicemedia/live/13561/56008/ 56008.pdf [Accessed 15 April 2014].
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Correspondence 6. Glesby MJ, Aberg JA, Kendall MA, Fichtenbaum CJ, Hafner R, Hall S, et al. Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers. Clin Pharmacol Ther 2005; 78:143–153. 7. Else L, Watson V, Tjia J, Hughes A, Siccardi M, Khoo S, et al. Validation of a rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for the simultaneous determination of existing and new antiretroviral compounds. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878:1455–1465.
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8. Zhou Y, Li J, He X, Jia M, Liu M, Li H, et al. Development and validation of a liquid chromatography-tandem mass spectrometry method for simultaneous determination of amlodipine, atorvastatin and its metabolites ortho-hydroxy atorvastatin and para-hydroxy atorvastatin in human plasma and its application in a bioequivalence study. J Pharm Biomed Anal 2013; 83:101– 107.
DOI:10.1097/QAD.0000000000000356
Should we not pay attention to what women tell us when they vote with their feet? We note with fascination that the authors of an article finding higher loss to follow up (LTF) in women presented with the so-called and misnamed ‘Option’ Bþ have concluded that ‘Decreasing LTF will improve the effectiveness of the Option Bþ approach’ [1]. Could we not also consider the explanation that women may be acting entirely rationally when not returning to a health facility that does not prioritize their sexual and reproductive rights? Women offered ‘Option Bþ’ are not being treated as ends in themselves, they are being used as a means to another end. As if receiving a diagnosis of HIV during pregnancy was not enough of a blow, women were not given counselling as to their options nor offered monitoring and treatment at a time that would maximize their long-term health and a securer future. Women might have more pressing concerns such as their immediate health and well being, stigmatization, genderbased violence [2] and everyday life to cope with. As ‘Option’ Bþ was foisted on women on the very same day as receiving their diagnosis with no time to gather their thoughts, what more could possibly improve LTF short of coercion? Thus, on the same findings, the authors might have concluded that decreasing the Option Bþ approach will improve the loss to follow up and effectiveness of antiretrovirals when they are required. Rather than concluding that ‘Tailored interventions, like community or family-based models of care could improve its [Option Bþ] effectiveness’, we believe that the authors might have considered that tailored interventions, such as highquality rational care based on the individual needs of the woman and her baby, could improve its (antiretroviral, ARV) effectiveness. The latter approach might be as empathic and effective as well as respecting human rights. We recommend a reappraisal of Option Bþ.
Acknowledgements AW is Founding Director of the Salamander Trust and Co-Founder and Co-Chair of the Sophia Forum, charities working for women living with HIV globally and in the UK. SB is a trustee of the Sophia Forum. Both are involved in a global community consultation for the WHO update of its 2006 Sexual and Reproductive Health and Human Rights Guidelines for women living with HIV.
Conflicts of interest There are no conflicts of interest. Susan Bewleya and Alice Welbournb, aWomen’s Health Academic Centre, King’s College London, London, UK, and bSalamander Trust, London, UK. Correspondence to Susan Bewley, MD, King’s College London, London SE1 7NH, UK. E-mail: [email protected] Received: 12 April 2014; revised: 27 May 2014; accepted: 29 May 2014.
References 1. Tenthani L, Haas AD, Tweya H, Jahn A, van Oosterhout J, Chimbwandira F, et al. Retention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women (‘Option BR’) in Malawi. AIDS 2014; 28:589–598. 2. Salamander Trust and Members of the Coalition of Women Living with HIV and AIDS in Malawi. Seeking safety: Stepping Stones in Malawi. https://vimeo.com/69251113 [Accessed 12 April 2014].
DOI:10.1097/QAD.0000000000000370
Skeletal muscle toxicity associated with emtricitabine/rilpivirine/tenofovir fixed-dose combination: a case report French, European and US guidelines recommend earlier initiation of combined anti-retroviral treatments (cART) [1–3]. Currently, cARTs are overall associated with fewer adverse events. Fixed dose combinations (FDCs) and single treatment regimen are more and more frequently used in HIV-infected patients because they are easier to take and thus considered to improve adherence.
However, hindsight is still needed to fully assess the rare adverse events. We describe here the first case of skeletal muscle toxicity associated with rilpivirine (RPV). A 63-year-old man was consulted in June 2013 for subacute weight gain, fatigue and muscular pain. He had an A1 stage past medical history of HIV infection since
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1985, with good immunologic profile and an undetectable plasma HIV-1 RNA for 12 years. His cART history began with zidovudine/lamivudine/abacavir FDC, continued with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF)/efavirenz (EFV) FDC during 12 years recently changed from January 2013 for FTC/TDF/RPV FDC due to lipid abnormalities. Apart from HIV, he had a stable history of heart angina. He also presented HCV infection successfully treated in 2011 with sustained viral response. He was a semi-professional swimmer and still recently in excellent physical condition. Since the last switch to TDF/FTC/RPV FDC, he rapidly complained of change in his body shape, a gain of 8 kg of abdominal fat, myalgia at mild efforts and proximal muscular loss.
(a)
(b)
Physical examination showed dual lipodystrophia with android obesity and amyotrophy of the proximal muscles. Creatine phosphokinase, aldolase and aspartate aminotransferase were normal. An abdominal computed tomographic scan showed inter-visceral fat accumulation. A muscular biopsy was performed and diagnosed a toxic myopathy with mitochondrial proliferations and cyclooxygenase (Cox)-negative fibres. There were no lipid inclusions, no vasculitis and no infiltrates. Tumour necrosis factor-alpha (TNF)-alpha and leptin circulating levels increased whereas adiponectin decreased during the acute cytopathy event (2.4, 5.6 and 4.2 pg/ml; 4.4, 5.7 and 4.5 ng/ml, respectively, before and during the cytopathy event). RPV, tenofovir and FTC concentrations 12 h after the last drug intake were at 377, 180, and 429 ng/ml, respectively. All were above the upper limit of acceptable concentrations. Consequently, RPV was discontinued in this patient and the EFV reinitiated with the same TDF/FTC backbone. Two months after the switch, the patient was doing well, no more complaining of fatigue and muscular pain; he has lost 6 kg in less than 2 weeks after switching. Circulating levels of TNF-alpha, leptin and adiponectin went back to normal values after the RPV switch (5.8, 3.6 and 5.3 mg/ml). Six months after the switch, he has now returned to his original weight (a total loss of 10 kg) and was able to practice swimming as well. Figure 1 presents disease slides with succinate dehydrogenase and Cox activities. RPV is a recently approved second-generation nonnucleoside reverse transcriptase inhibitor, marketed in coformulation with TDF and FTC in fixed-dose combination. It has demonstrated its noninferiority when compared with EFV as a first-line therapy and is an attractive option for switching therapy. Since the first clinical trials in 2008 and its approval in 2011, RPV has shown an excellent safety profile, compared in particular to EFV. The latest follow-up at 96 weeks has shown few neurologic or psychiatric symptoms, dermatologic abnormalities and mild changes in total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride
Fig. 1. Histo-Enzymology on frozen section of deltoid muscle fragment. (a) Succinate dehydrogenase activity (arrow show fiber with mitochondrial proliferation). (b) Cyclooxygenase (Cox) activity (arrow show fiber with no Cox activity).
[4,5]. A case report of severe induced hepatitis on RPV has been published [6,7]. We describe here, to our knowledge, the first case of muscle toxicity associated with a FDC containing RPV. Although we have no clear causal relationship, the accountability of RPV is strong because it was the only changed drug during this period, and its discontinuation has led to an improvement of the symptoms. It was not ruled out whether this adverse event was the result of an excessive concentration or an intrinsic property of RPV. Both EFV and RPV plasma concentrations were above the respective toxicity cut-offs (4000 and 300 ng/ml, respectively). For EFV, such high concentrations might be explained by Cytochrome P450 2B6 genetic polymorphism. For RPV, the recent HCV liver disease (despite the successful treatment in 2011 and any significant fibrosis) might be an explanation of the higher plasma exposure observed. To conclude, even with new FDC regimens considered to be much better tolerated than previous ART regimens, data regarding follow-up of the new drugs are still scarce. This case report describes the first case of skeletal muscle toxicity. Our data suggest that it could be dose-dependent. Plasma concentrations must be of
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Correspondence
interest when adverse events are suspected to rule out toxicity.
Correspondence to Liem Binh Luong Nguyen, Infectious Diseases Department, Bichat Claude Bernard Hospital, 46 rue Huchard, 75018 Paris. E-mail: [email protected]
Acknowledgements
Received: 27 May 2014; revised: 13 June 2014; accepted: 23 June 2014.
Conflicts of interest S.H. has received travel grants from BMS and MSD. G.P. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers-Squibb, Gilead Sciences, Janssen, Merck, ViiV Healthcare and Splicos. Y.Y. is a board member and reports receiving consultancy honoria from Abbott, BMS, Gilead, MSD, Roche, Tibotec and ViiV Healthcare; he also reports receiving honoraria for development of educational presentations from Abbott, BMS, Gilead, Tibotec and ViiV Healthcare. F.X.L. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers-Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. Liem Binh Luong Nguyena, Stanislas Harent a, Gilles Peytavinb,c, Benoit Visseauxb,d, Jean P. Bastarde, Odile Dubourgf, Sylvie Larivena, Patrick Yenia, Yazdan Yazdanpanaha,b and Francois X. Lescurea,b, a Infectious Diseases Department, Bichat Claude Bernard Hospital, bIAME, UMR 1137, INSERM, Universite´ Paris Diderot, cUF 301 Pharmaco-Toxicology Department, Bichat Claude Bernard Hospital, dLaboratoire de Virologie, Bichat Hospital, eBiochemistry Department, Tenon Hospital, and fNeuropathology Department, Pitie´-Salpetrie`re Hospital, AP-HP, Paris, France.
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References 1. Philippe M. Prise en charge me´dicale des personnes vivant avec le VIH [Medical Management of people living with AIDS, Documentation Franc¸aise]. La documentation franc¸aise 2013. 2. Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the international antiviral society – USA panel. JAMA 2012; 308:387–402. 3. EACS. Guidelines for treatment of HIV-infected adults in Europe. 2013. http://eacsociety.org/Guidelines.aspx 4. Cohen CJ, Molina J-M, Cahn P, Clotet B, Fourie J, Grinsztejn B, et al., THRIVE Study Group. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr 2012; 60:33–42. 5. Cohen CJ, Molina J-M, Cassetti I, Chetchotisakd P, Lazzarin A, Orkin C, et al., ECHO, THRIVE study groups. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS 2013; 27:939–950. 6. Ahmed Y, Siddiqui W, Enoch CB, Albrecht H, Bookstaver PB. Rare case of rilpivirine-induced severe allergic hepatitis. J Antimicrob Chemother 2013; 68:484–486. 7. Casado JL. Liver toxicity in HIV-infected patients receiving novel second-generation nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine. AIDS Rev 2013; 15:139–145.
DOI:10.1097/QAD.0000000000000387
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