Methadone dosing in patients on ritonavir-boosted-based highly active antiretroviral therapy

Lozano, Roberto; Domeque, Nieves; Frutos, Alberto Jose

doi:10.1016/j.medcli.2018.03.004

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e.g. combinations of RTV with atazanavir, lopinavir or darunavir) and extensively metabolized by cytochrome P450 (CYP) 3A4 for which is a potent inhibitor.<a class="elsevierStyleCrossRef" href="#bib0035">2</a> Also, we know that MTD is mainly metabolized by CYP 3A4 and CYP 2B6 to which it potently induces.<a class="elsevierStyleCrossRef" href="#bib0040">3</a> Therefore, the sharing of the CYP 3A4 metabolic pathway, results in a metabolism-based DDI, between MTD and RTV.Despite being a well-known DDI, the mechanism by which RTV alters the clearance of MTD remains controversial, so is its influence on plasma MTD levels. Which finally manifests in form of great variability in the dosage of MTD, when used in conjunction with RTV: from not modifying the dose of MTD until increases up to 40%.<a class="elsevierStyleCrossRef" href="#bib0045">4</a>Thus, we aimed to analyze the influence of ritonavir-based HAART on MTD-dose of patients included in MMT programs, in order to avoid the variability of its dosage.For this, a retrospective observational clinical study was conducted. The initial sample was composed of HIV(+)-patients treated with HAART and included in our MMT program, during a 10-years follow-up period (n=130). Since it was not an experimental work no ethic committee review was required. However, it did need to meet the ethical standards of the Declaration of Helsinki.Firstly, we collected data of clinically relevant metabolism-based drug-drug interactions (DDI) between ARVs and MTD. The results showed that 26% of patients display ARVs–MTD interactions, of which the MTD–RTV interaction (23%) was the most prevalent. Secondly, after excluding patients (n=15) who had MTD interactions with drugs other than RTV we obtained the study final sample (n=115).From this final sample, we compared the mean value of the MTD-dose, adjusted by body weight, of HIV(+)-patients on RTV-based HAART (RTV-group; RTV dose of 100–200mg/day; n=35) vs. of HIV(+)-patients on HAART that excluded RTV (non-RTV-group; n=80). As result, we found that average MTD-dose in the RTV-group was 50% higher than non-RTV-group (1.2±0.5mg/kg vs 0.8±0.5mg/kg, 95% CI=0.199 to 0.601, p<.0001), <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>These data coincide with those of the authors who reported a significant decrease in plasma MTD values (up to 40%),<a class="elsevierStyleCrossRef" href="#bib0045">4</a> when used in conjunction with RTV; also, support the observations of Kharasch et al.,<a class="elsevierStyleCrossRef" href="#bib0050">5</a> that CYP3A does not mediate the interaction between MTD and RTV. In addition, the results suggest that RTV would first inhibit CYP3A4, increasing plasma MTD levels and, this increase, in turn, would secondarily cause an increase in the self-induction of CYP2B6. Thus, the MTD-inhibition of CYP3A4 together with the self-induction of CYP2B6, would result in an overall decrease of plasma MTD levels; which, ultimately, could lead to opiate withdrawal symptoms (for example, fatigue, anxiety, restlessness), and cause patients to require higher doses of MTD.In conclusion, up to date, MTD-RTV continues to be the most prevalent DDI among HIV(+)-patients receiving HAART and included in MMT programs. These patients, due to the decrease of the values of MTD in plasma when administered in conjunction with RTV-boosted-based HAART (100–200mg/day), need to increase their dose of MTD (mg/kg-body weight) by 50%.Finally, it should be noted, as the most important limitation of this DDI analysis and due to the size of the sample and the absence of data, that it could not evaluate the influence of other factors, such as sex, age, the different combination of ARVs, and concomitant treatments for other infectious and psychiatric co-morbidities." "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ABV: abacavir; ARV: antiretroviral; ATV: atazanavir; DRV: darunavir; EFV: efavirenz; FTC: emtricitabine; HAART: highly active antiretroviral therapy; HIV: human immunodeficiency virus; LPV: lopinavir; MTD: methadone; NVP: nevirapine; RTV: ritonavir; RTG: raltegravir; 3TC: lamivudine; TDF: tenofovir; BMI: Body Mass Index." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RTV-group (N=35) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-RTV-group (N=80) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Patients characteristics, mean (SD)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Female, No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 (30) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age, years old \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 (8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49 (8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weight, kg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">64 (10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70 (15) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BMI, kg/m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 (4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 (5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MTD-dose/weight, mg/kg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.2 (0.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8 (0.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">HAART (ARVs combinations; between brackets, [RTV-boosted ARVs]), N(%)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">EFV-FTV-TDF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51 (64) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FTC-TDF-NVP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (13) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FTC-TDF-RTG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (4.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3TC-ABV-EFV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Non-ART \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 (14.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FTC-TDF-[DRV-RTV] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 (48.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FTC-TDF-[ATZ-RTV] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (26) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FTC-TDF-[LPV-RTV] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3TC-ABV-[LPV-RTV] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (8.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3TC-ABV-[ATV-RTV] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1950308.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Patients characteristics and antirretroviral drug regimens." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacological maintenance treatments of opiate addiction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J. 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