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Factors affecting antiretroviral pharmacokinetics in HIV-infected women with virologic suppression on… Loutfy, Mona R; Walmsley, Sharon L; Klein, Marina B; Raboud, Janet; Tseng, Alice L; Blitz, Sandra L; Pick, Neora; Conway, Brian; Angel, Jonathan B; Rachlis, Anita R; Gough, Kevin; Cohen, Jeff; Haase, David; Burdge, David; Smaill, Fiona M; de Pokomandy, Alexandra; Loemba, Hugues; Trottier, Sylvie; la Porte, Charles J Jun 3, 2013

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RESEARCH ARTICLE Open AccessFactors affecting antiretroviral pharmacokineticsin HIV-infected women with virologic suppressionon combination antiretroviral therapy:a cross-sectional studyMona Rafik Loutfy1,2*, Sharon Lynn Walmsley2,3, Marina Barbara Klein4, Janet Raboud3,5, Alice Lin-in Tseng3,6,Sandra Lauren Blitz3, Neora Pick7,8, Brian Conway9, Jonathan Benjamin Angel10,11, Anita Rochelle Rachlis2,12,Kevin Gough2,13, Jeff Cohen14, David Haase15,16, David Burdge7,17, Fiona Mary Smaill18,Alexandra de Pokomandy4,19, Hugues Loemba10,20, Sylvie Trottier21 and Charles Jean la Porte10,11AbstractBackground: Although some studies show higher antiretroviral concentrations in women compared to men, dataare limited. We conducted a cross-sectional study of HIV-positive women to determine if protease inhibitor (PI) andnon-nucleoside reverse transcriptase inhibitor (NNRTI) Cmin and Cmax values were significantly different thanhistorical general population (predominantly male) averages and to evaluate correlates of higher concentrations.Methods: HIV-positive women with virologic suppression (viral load < 50copies/mL) on their first antiretroviralregimen were enrolled. Timed blood samples for Cmin and Cmax were drawn weekly for 3 weeks. The ratio of eachindividual’s median Cmin and Cmax to the published population mean values for their PI or NNRTI was calculatedand assessed using Wilcoxon sign-rank. Intra- and inter-patient variability of antiretroviral drug levels was assessedusing coefficient of variation and intra-class correlation. Linear regression was used to identify correlates of thesquare root-transformed Cmin and Cmax ratios.Results: Data from 82 women were analyzed. Their median age was 41 years (IQR=36-48) and duration ofantiretrovirals was 20 months (IQR=9-45). Median antiretroviral Cmin and Cmax ratios were 1.21 (IQR=0.72-1.89,p=0.003) (highest ratios for nevirapine and lopinavir) and 0.82 (IQR=0.59-1.14, p=0.004), respectively. Nevirapine andefavirenz showed the least and unboosted atazanavir showed the most intra- and inter-patient variability. HigherCD4+ count correlated with higher Cmin. No significant correlates for Cmax were found.Conclusions: Compared to historical control data, Cmin in the women enrolled was significantly higher whereasCmax was significantly lower. Antiretroviral Cmin ratios were highly variable within and between participants. Therewere no clinically relevant correlates of drug concentrations.Trial registration: NCT00433979Keywords: HIV, Women, Antiretroviral therapy, Pharmacokinetics* Correspondence: mona.loutfy@wchospital.ca1Women’s College Research Institute, Women’s College Hospital, 790 BayStreet, Room 736, Toronto, Ontario M5G 2N8, Canada2Department of Medicine, University of Toronto, Toronto, Ontario, CanadaFull list of author information is available at the end of the article© 2013 Loutfy et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Loutfy et al. BMC Infectious Diseases 2013, 13:256http://www.biomedcentral.com/1471-2334/13/256BackgroundSince the advent of combination antiretroviral therapy(cART), there has been a dramatic decrease in the mor-tality of individuals infected with human immunodefi-ciency virus (HIV) [1]. Traditionally, this combinationhas included two drugs from the antiretroviral class ofnucleoside reverse transcriptase inhibitors (NRTIs) andeither one from the class of protease inhibitors (PIs) orone from the class of non-nucleoside reverse transcript-ase inhibitors (NNRTIs) [2]. If the third agent is fromthe PI class, it is often combined with a low dose of rito-navir in order to boost its drug levels [2]. More recently,raltegavir has been added as an option for the thirdagent, but remains rarely used in Canada due to cost [3].Despite these tremendous advances in HIV manage-ment, there remain several important complications re-lated to antiretroviral drug use, one of the most notablebeing drug-related adverse events (AEs) and toxicities [4],which can negatively impact patients’ quality of life, con-tributing to non-adherence and drug resistance and ultim-ately effectiveness. Adverse drug reactions to antiret-rovirals are a major reason for discontinuing or changingtherapy [5,6]. Furthermore, these drug-related complica-tions can significantly contribute to morbidity, hospitaliza-tions, and mortality in this population [7-10].Women constitute one of the fastest-rising populationgroups at risk for infection with HIV, representing over50% of cases worldwide, and approximately 25% of newcases in the United States (U.S.) and 28% of new casesin Canada [1-3]. Surprisingly, little is known about thedifferential efficacy and toxicity of various antiretroviraldrugs in women compared to men [11]. This gap inknowledge is a result of the initial exclusion and contin-ued underrepresentation of women in antiretroviral clin-ical trials [12]. This circumstance has slowly started tochange, and there are now more longitudinal studiesexamining women-specific issues [13,14]. Many studiesin the general population have shown that AEs are morecommon in women than in men [15]. In the HIV-infected population, higher incidence rates of increasedsystemic symptoms (such as nausea, vomiting and diar-rhea), as well as organ toxicity (including anemia, hep-atotoxicity, pancreatitis, lactic acidosis, peripheralneuropathy, and notable lipodystrophy), have been ob-served in women compared to men [11,16,17]. For nevi-rapine, female gender and higher CD4+ cell counts wererisk factors for fatal hepatitis, and this observation hasled regulatory authorities to release warnings on its usein certain female populations [18].Most of these studies assessing sex differences in anti-retroviral AEs rates are limited in that they only identifythe issue of increased toxicity in women and do not try toelucidate the cause or management [16,19,20]. The poten-tial causes of these gender differences in antiretroviraltoxicities may have a sound biologic basis possibly relatedto differences in physiology and/or the influence of sexhormones on drug metabolism. All aspects of drug hand-ling and exposure may be different in women versus men,including bioavailability (with lower gastric emptying timedue to hormonal contraception use or pregnancy) and dis-tribution (lower body weight, smaller organ size, higherbody fat content, altered gastric motility, greater organblood flow, and altered protein binding secondary to en-dogenous or exogenous estrogens). Metabolism and elim-ination of drugs have also exhibited gender differencesrelated to differences in expression and activity of variousdrug transporters and metabolizing enzymes [20,21]. Ofparticular interest, a better understanding of antiretroviralpharmacokinetics (PK) in women and how these druglevels impact AEs and toxicities in women is crucial, andwill lead to more effective methods of treatment, reduceddiscomfort, possible enhanced adherence and improvedmorbidity and/or mortality.Although a few investigations have considered PK differ-ences that occur between men and women, most of thesestudies involved the use of older antiretroviral agents andwere assessed in small sample sizes [21-29]. Furthermore,a number of potentially confounding variables such asrace, age, weight, menstruation, and hepatitis co-infectionhave not been explored as determinants impacting druglevels in a female population. We conducted a cross-sectional study of HIV-positive women taking their firstcombination ART to determine if drug levels (Cmin andCmax) of currently used PIs and NNRTIs were significantlyhigher in this population as compared to the historicalgeneral (predominantly male) population and to evaluatecorrelates of higher concentrations.MethodsEthics statementThe study was reviewed and received ethics approval bythe Full Institutional Research Ethics Board (REB) ofmain coordinating research centre, Women’s College Re-search Institute, Toronto, Canada (REB# 2006–003).Additional Full Institutional REB approval was obtainedfrom each research site prior to commencement. Allstudy personnel were trained in and practiced under theprinciples of the Declaration of Helsinki. All study can-didates were informed about this study and written in-formed consent was obtained from every participantprior enrollment.Study populationWe carried out a cross-sectional study with participantswho met the following inclusion criteria: 1) HIV-positive,2) biologically female, 3) 18 years of age or older, 4)taking their first cART regimen containing either a PI oran NNRTI with a backbone of NRTI as per commonLoutfy et al. BMC Infectious Diseases 2013, 13:256 Page 2 of 10http://www.biomedcentral.com/1471-2334/13/256practice for at least 3 months (but could have had priorswitches that were not due to virologic failure), 5) takingeither a PI or an NNRTI but not both, 6) if taking a PI,must have been taking only one PI excluding low dose ri-tonavir used as boosting and 7) had evidence of full viro-logic suppression (HIV-1 RNA VL < 50 copies/mL) on atleast two occasions at least one month apart. The patientpopulation was limited to women who were on their firstcART regimen in order to ensure a more homogeneouspopulation. The current analysis was limited to candidateswho were taking the following antiretroviral drugs(atazanavir, atazanavir boosted with ritonavir, lopinavirboosted with ritonavir, efavirenz and nevirapine) [3,30].Participants could not take both a PI and NNRTI or twoPIs excluding ritonavir as there are multiple drug interac-tions between these agents which would lead to uninter-pretable results. Further, participating women had to havefull virologic suppression to avoid inclusion of womenwho experience difficulty with drug adherence. The 3month requirement for being on a cART regimen wasmandated to 1) ensure stabilization of adherence as theremay be an adjustment period as patients get accustomedto taking their new drug regimen, 2) eliminate early dis-continuations due to drug toxicities which often happenduring the first 3 months of therapy, and to a lesser extend3) to ensure drug steady state as there is some variationbetween drugs [5].A planned sample size of 80 was calculated in order toestimate if the mean ratio of the Cmin values to historicalvalues for the general population was significantly differ-ent from 1.0, assuming an alternative hypothesis of 1.2with a standard deviation of 0.64, 80% power and a sig-nificance level of 0.05. Recruitment was conducted fromFebruary, 2007 to November, 2008 from 14 primary careand specialty HIV clinics from across Canada. Recruit-ment and study qualification determination was carriedout by the site investigator and research staff. The re-cruitment was carried out in a non-random consecutivemanner as research staff were instructed to invite everyconsecutive qualifying woman who received services intheir clinic on all days that care was provided.Data collectionStudy visits occurred at weekly intervals for a three-week period. During the baseline visit, demographic andHIV and other medical history data was collected includ-ing concurrent medications, validated questionnairespertaining to antiretroviral adherence [31] and symptomdistress [32] were completed, weight was measured andblood work to assess laboratory values was drawn.Pharmacokinetic analysisAt each of the three visits, patients had a pre-dose (Cmin)and a maximum (Cmax) PI or NNRTI drug level drawn.Patients were asked to fast from midnight of the previ-ous night. One hour before their scheduled morningdose the pre-dose blood collection was drawn (Cmin t)(alternative arrangements were made if the patient tookher drugs in the evening). Following the pre-dose bloodcollection, patients consumed a standard breakfast(consisting of 50% carbohydrate, 30% fat, 20% protein)after which time the morning antiretroviral dose was ad-ministered. Cmax levels were drawn at 2 hours post-dosefor atazanavir 400 mg QD [33], 3 hours post-dose foratazanavir/ritonavir 300/100 mg QD [33], 4 hours post-dose for lopinavir/ritonavir 400/100 mg BID [34], 5hours post-dose for efavirenz 600 mg QD [35], and 2hours post-dose for nevirapine (both 200 mg BID and400 mg QD [36]). The plasma drug level samples wereall stored in cryovials at −20°C or lower and shipped forconcurrent assessment at the end of the study. Concen-trations of the PIs and the NNRTIs in plasma were mea-sured simultaneously by sensitive and selective, validatedhigh-performance liquid chromatography coupled totandem mass-spectroscopy (LC-MS/MS) [37]. All sam-ples were analyzed at the pharmacokinetic laboratory atthe Ottawa Hospital Research Institute in Ottawa,Canada.The PK endpoints for each patient were determinedby taking the median of the three weekly values for theCmin and Cmax. The rationale for measuring drug levelsat three separate time points was that there is potentiallyintra-individual variability in drug levels, especially forPIs [38,39]. Using the median value for the endpointseliminated outliers. The three drug level measurementsallowed for the calculation of intra-patient variability.Statistical analysesBaseline characteristics of the study population weresummarized using medians and interquartile ranges(IQR) for continuous variables and frequencies and pro-portions for categorical variables.The mean Cmin and Cmax drug levels in the historicalHIV population were taken from the most recent prod-uct monograph when possible, or from a published studyif the product monograph did not report these values[33-36]. Next, for each subject the ratio of their medianCmin and Cmax for their main PI or NNRTI to this pub-lished drug level was calculated and used as the primaryoutcome as previously reported by Burger et al. [40] Dueto the lack of published population PK data for ritonavirwhen included as part of regimen in a “boosting” role,we only calculated the ratios for the main PI in a partici-pant’s regimen. Differences between the Cmin ratio andCmax ratio to the population mean were conducted usinga Wilcoxon sign-rank test for a median of 1. For com-parison purposes, PK levels were dichotomized into highand low levels with a high level defined as ≥ 1.5 XLoutfy et al. BMC Infectious Diseases 2013, 13:256 Page 3 of 10http://www.biomedcentral.com/1471-2334/13/256arithmetic population mean of the Cmin and Cmax foreach drug. Inter-patient variability of Cmin and Cmax foreach antiretroviral drug was assessed by calculating thecoefficient of variation (CV) using each individual’s me-dian Cmin and Cmax. An intra-patient CV for each par-ticipant was calculated from the Cmin and Cmax valuesobtained at each of the 3 visits. These values are summa-rized using median and IQR of the individual CVs. Theinter-patient CV is a measure of variation among indi-viduals whereas intra-patient CV measures variationwithin an individual The inter-patient CV is calculatedas the ratio of the standard deviation to the mean X 100;the higher the value, the more variability exists. Finally,linear regression models were fit to assess correlates ofthe square root-transformed Cmin and Cmax ratios. Thesquare-root transformation was used because the un-transformed Cmin and Cmax ratios were both right-skewed. The regression models included indicator vari-ables to account for the different antiretroviral medica-tions and each potential correlate was includedseparately in an adjusted model. Statistical analyses wereperformed using SAS Version 9.2 (SAS Institute, Cary,North Carolina, USA).ResultsStudy populationNinety women were enrolled from 14 sites acrossCanada between 2/2007 and 11/2008. Eight women wereexcluded for the following reasons: one due to missingdata, six were not on a current cART regimen deemedeligible to be included in this analysis, and one becauseshe was not on standard dosing schedule. The data issummarized for the remaining 82 patients. Median ageof the study population was 41 years (IQR 36–48) and56% identified as Black. The median times since theirHIV diagnosis and start of their current cART regimenwere 7 years (IQR 3–11) and 20 months (IQR 9–45), re-spectively. Fifty-seven percent were taking a PI-containing regimen (81% being ritonavir-boosted and19% unboosted) and 43% a NNRTI-containing regimen.All participants had an undetectable viral load with amedian CD4+ count at the time of enrolment of 487cells/μL (IQR 380–621). Additional demographic andclinical variables of the study population are summarizedin Table 1. No relevant concurrent medications were be-ing taken by the participants.Drug level ratios by antiretroviral drugThe Cmin and Cmax summaries and historical values usedto calculate the ratios are reported in Table 2 [33-36].Paired values for the Cmin and Cmax data for each dosingregime are shown in Figure 1. Overall, the median ratioof the participants’ Cmin to historical mean values was1.21 (IQR 0.72-1.89, p=0.003) and the median ratio ofCmax to historical mean values was 0.82 (IQR 0.59-1.14,p=0.004). Twenty-eight participants (34%) had Cmin ≥1.5 X arithmetic population mean of the Cmin for eachdrug and seven participants (9%) had Cmax ≥ 1.5 X arith-metic population mean of the Cmax for each drug; all onan NNRTI. The median ratios of Cmin and Cmax to his-torical mean values for each specific antiretroviral drugoverall and for each dose are presented in Table 3.Intra-patient and inter-patient variability of antiretroviraldrug levelsThe intra- and inter-patient variability of each antiretro-viral drug’s Cmin and Cmax was assessed using CV; dataTable 1 Demographic characteristics of study participantsCharacteristics Total n=82Age 41 (36–48)RaceWhite 28 (34%)Black 46 (56%)Other 8 (10%)Risk FactorInjection drug use 11 (13%)Endemic country 27 (33%)Heterosexual contact 59 (72%)Blood transfusion 7 (9%)Unknown 8 (10%)Years since HIV diagnosis 7 (3–11)CD4+ cell count prior to cART (μL) 232 (128–400)Current CD4+ cell count (μL) 487 (380–621)VL prior to cART (log10 copies/mL) 4.5 (3.0-5.0)AIDS diagnosis 19 (23%)Months since start of cART 20 (9–45)cART includes PI 47 (57%)cART includes NNRTI 35 (43%)Missed ARV dose in past week 6 (7%)Hepatitis B co-infection 2 (2%)Hepatitis C co-infection 10 (12%)Weight (kg) 67.3 (60.3-81.5)BMI 25.8 (22.4-31.3)Menstrual statusRegular periods 44 (54%)Irregular periods 10 (12%)Current amenorrhea 9 (11%)Menopausal 19 (23%)Continuous variables presented as medians with interquartile range;categorical variables presented as n (%).VL, viral load; AIDS, acquiredimmunodeficiency syndrome; cART, combination antiretroviral therapy; PI,protease inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; ARV,antiretroviral; BMI, body mass index.Loutfy et al. BMC Infectious Diseases 2013, 13:256 Page 4 of 10http://www.biomedcentral.com/1471-2334/13/256are presented in Table 4. Data from 2 participants forwhom PK samples were only obtained at one visit wereexcluded from the intra-patient variability calculations.Nevirapine BID and lopinavir/ritonavir BID showed theleast inter-patient variability with the lowest CVs forboth Cmin and Cmax. Nevirapine BID and efavirenz hadthe lowest intra-patient variability variability for Cmin,while nevirapine BID, lopinavir/ritonavir BID, andefavirenz demonstrated lowest intra-patient variabilityfor Cmax. Inter- and intra- patient variability washigh for atazanavir, particularly when not boosted withritonavir.Linear regression models for antiretroviral Cmin and CmaxLinear regression models to assess the relationship be-tween the square root-transformed Cmin ratio and demo-graphic and clinical variables of the population werecarried out (Table 5). Higher CD4+ cell count was theonly variable significantly associated with higher Cmin ra-tios (Beta coefficient=0.04/ 100 cells per μL increase,Table 2 Reference population mean and Study Participants Cmin and Cmax by antiretroviral drugCmin CmaxAntiretroviral agent* Reference Dose (mg) Freq N Populationmean (ug/mL)Study participantsmedian (IQR)Populationmean (ug/mL)Study participantsmedian (IQR)Atazanavir** [33] 400 QD 9 273 214 (95–373) 3152 1870 (979–2950)Atazanavir** boosted with ritonavir [33] 300 QD 18 862 835 (663–1220) 5233 3430 (2670–4450)Lopinavir boosted with ritonavir [34] 400 BID 16 5500 6660 (4360–7710) 9800 8420 (7240–11600)Lopinavir boosted with ritonavir [34] 800 QD 4 1700 6445 (2452–8260) 11800 11685 (7403–14900)Efavirenz [35] 600 QD 16 1768 1680 (1180–3450) 4072 3235 (2330–5180)Nevirapine [36] 200 BID 11 3730 5270 (3380–7190) 5740 5510 (4810–7860)Nevirapine [36] 400 QD 8 2880 5995 (2590–7275) 6690 6400 (4838–9380)QD, once daily; BID, twice daily; IQR, interquartile range.*Nucleos(t)ide backbone: of 9 participants on Atazanavir 400 mg QD, all 9 were taking Abacavir/3TC; of 18 participants on Atazanavir/ritonavir 300 mg/100 mgQD, 11 were taking Abacavir/3TC, 3 Tenofivir/FTC, 3 Tenofivir/3TC and 1 Zidovudine/3TC; of 16 participants on Lopinavir/ritonavir 400 mg/100 mg BID, 7 weretaking Zidovudine/3TC, 6 Abacavir/3TC, 1 Tenofivir/FTC, 1 Tenofivir/3TC and 1 was on PI monotherapy; of 4 participants on Lopinavir/ritonavir 800 mg/200 mg QD,2 were taking Tenofivir/FTC, 1 Abacavir/3TC, 1 Didanosine/3TC; of 16 participants on Efavirenz 600 mg QD, 5 were taking Tenofivir/FTC, 5 Abacavir/3TC, 5Zidovudine/3TC, 1 Tenofovir/3TC; of 11 participants on Nevirapine 200 mg BID, 7 were taking Zidovudine/3TC, 4 Abacavir/3TC; of 8 participants on Nevirapine 400mg/ QD, 4 were taking Abacavir/3TC, 1 Tenofivir/FTC, 1 Zidovudine/3TC, 1 Tenofivir/3TC, 1 Didanosine/3TC.** Of the 27 particpants taking Atazanavir or Atazanvir/ritonavir, none were taking any gastric acid suppression medication.Figure 1 Paired Cmin and Cmax values for each participant by antiretroviral drug and dose. The Cmin values are identified by circles and theCmax values by triangles. The reported population mean Cmin and Cmax values for each antiretroviral drug and dose are presented with thehatched lines (−−−).Loutfy et al. BMC Infectious Diseases 2013, 13:256 Page 5 of 10http://www.biomedcentral.com/1471-2334/13/25695% CI=0.003-0.080; p=0.03). Similar analyses were car-ried out for the assessment of the correlates of thesquare root-transformed Cmax ratios and only injectiondrug use showed a trend to be negatively associated withCmax ratio (Beta coefficient=−0.10, 95% CI=−0.23-0.02;p=0.10).DiscussionIn this cross-sectional study of 82 HIV-positive womentaking cART with full virologic suppression, median pre-dose drug levels were found to be significantly higherthan historical controls. Approximately one- third ofwomen had a Cmin value more than 1.5 times higherthan historical control values. Since the majority of his-torical controls consist of men, this finding supports thegrowing literature indicating that drug levels are higherin women than in men.Our findings also support the increasing body of litera-ture on the gender differences in drug disposition andPK of all drugs. However, in the HIV population, thesedifferences may in part be due to race as many of thehistorical controlled participants were White men, andas in our study, many of the females infected with HIVglobally are Black. Several studies have investigated therelationship of antiretroviral PK with genetically deter-mined factors that might differ by individual ancestralhistory [41-45]. Racial differences have been found in P-glycoprotein (PGP) activity, an efflux protein whichpumps its substrates, including the PIs, out of cells, awayfrom their site of action. For example, Africans are fourtimes more likely than white Americans or Japanese in-dividuals to have the CC genotype at position 3435 ofthe gene coding for PGP [45]. Fellay and colleagues [41]demonstrated that persons with the CC genotype havehigher PGP-activity, higher serum drug levels. Similarly,there are racial differences in the prevalence of slow-metabolizers of specific pathways, for example 2D6 and2B6, of the cytochrome P-450 system of drug metabol-ism in the liver [43]. Thus, there may be genetically de-termined heterogeneity in the in vivo transport andmetabolism of antiretroviral agents, resulting in variationin serum and intracellular drug levels.Table 3 Ratio of Cmin and Cmax values to Historical Population Means by antiretroviral drug and doseCmin CmaxAntiretroviral agent n n (%) >1.5historicalpop MeanMedia ratio tohistorical population meanmedian ratio (IQR)p-valuea n (%) >1.5Historicalpop meanMedia ratio tohistorical population meanMedian ratio ( IQR)p-valueaAll 82 28 (34.1%) 1.21 (0.72-1.89) <.01 7 (8.5%) 0.82 (0.59-1.14) <.01Atazanavir 400 QD 9 2 (22.2%) 0.78 (0.35-1.37) 0.71 0 (0.0%) 0.59 (0.31-0.94) 0.04Atazanavir (boosted with ritonavir) 300 QD 18 4 (22.2%) 0.97 (0.77-1.42) 0.58 0 (0.0%) 0.66 (0.51-0.85) <.001All Atazanavir 27 6 (22.2%) 0.95 (0.53-1.42) 0.76 0 (0.0%) 0.65 (0.44-0.87) <.0001Lopinavir (boosted with ritonavir) 400 BID 16 3 (18.8%) 1.21 (0.79-1.40) 0.27 0 (0.0%) 0.86 (0.74-1.18) 0.32Lopinavir (boosted with ritonavir) 800 QD 4 3 (75.0%) 3.79 (1.44-4.86) 0.25 0 (0.0%) 0.99 (0.63-1.26) 0.63All Lopinavir 20 6 (30.0%) 1.22 (0.79-1.81) 0.11 0 (0.0%) 0.86 (0.72-1.21) 0.29Efavirenz 600 DQ 16 6 (37.5%) 0.95 (0.67-1.95) 0.37 4 (25.0%) 0.79 (0.57-1.27) 0.63Nevirapine 200 BID 11 5 (45.5%) 1.41 (0.91-1.93) 0.03 2 (18.2%) 0.96 (0.84-1.37) 0.46Nevirapine 400 QD 8 5 (62.5%) 2.08 (0.90-2.53) 0.08 1 (12.5%) 0.96 (0.72-1.40) 0.95All Nevirapine 19 10 (52.6%) 1.62 (0.91-2.32) <0.01 3 (15.8%) 0.96 (0.81-1.37) 0.47IQR, Interquartile range. a Sign rank test for a median ratio different than 1.Table 4 Inter-patient and Intra-patient variability of Cmin and Cmax for each antiretroviral agentCmin CmaxAntiretroviral agent n Mean (SD) Inter-patient CV Intra-patient CVmedian (IQR)Mean (SD) Inter-patient CV Intra-patient CVmedian (IQR)Atazanavir 400 QD 9 250.4 (195.4) 78.0% 57.4 (40.5-86.7) 2000.4 (1145.5) 57.3% 61.9 (44.2-66.0)Atazanavir (boosted with ritonavir) 300 QD 18 1065.6 (699.2) 65.6% 26.3 (15.6-56.1) 3525.3 (1459.1) 41.4% 32.7 (17.2-54.5)Lopinavir (boosted with ritonavir) 400 BID 16 6370.0 (2846.4) 44.7% 23.8 (12.8-75.8) 8991.3 (2953.3) 32.8% 14.0 (12.3-21.7)Lopinavir (boosted with ritonavir) 800 QD 4 5356.2 (3882.3) 72.5% 63.4 (35.2- 115) 11151.3 (4433.2) 39.8% 15.6 ( 7.4-28.4)Efavirenz 600 QD 16 2196.9 (1209.2) 55.0% 17.7 (10.5-25.1) 3929.4 (2060.6) 52.4% 15.5 (12.8-27.9)Nevirapine 200 BID 11 5693.6 (2586.8) 45.4% 13.9 (10.2-27.8) 6490.9 (2454.9) 37.8% 10.7 ( 7.8-19.6)Nevirapine 400 QD 8 5027.9 (2867.2) 57.0% 21.3 (12.1-44.9) 6924.4 (2761.1) 39.9% 22.8 ( 8.3-53.8)SD, Standard deviation; CV, Coefficient of Variation; IQR, Interquartile Range.Loutfy et al. BMC Infectious Diseases 2013, 13:256 Page 6 of 10http://www.biomedcentral.com/1471-2334/13/256A number of other studies have assessed the genderdifferences in antiretroviral PK, particularly of the olderPIs. In a study of 186 patients (15.6% female), Fletcherand colleagues [23] demonstrated that serum levels ofsaquinavir were significantly higher in women than inmen, independent of body size. Another study sought tocharacterize the PK of saquinavir (1000 mg BID),lopinavir (400 mg BID), and ritonavir (100 mg BID) in amultidrug rescue therapy study [24]. Twenty-five pa-tients (28% women) were included in the study groupand fifteen (20% women) were included in the compari-son group that did not receive saquinavir. Area underthe curve (AUC), Cmax, and Cmin values for saquinavirand ritonavir were significantly higher in women than inmen, though there were no significant differences inweight or body mass indexes between genders. Work byDickinson and colleagues, who looked at the PK of saquin-avir and ritonavir in 34 patients on this combination,showed that in women a higher exposure to saquinavirmight, at least in part, be driven by higher exposure to ri-tonavir [25]. Pharmacokinetic studies of newer PIs haveonly been reported in product monographs limited to datashowing that women have modest increases in AUC of ap-proximately 20% for lopinavir, atazanavir and darunavir[33,34,46]. In terms of NNRTIs, investigators have demon-strated higher serum efavirenz and nevirapine levels inwomen [26-29]. A previous report using a full 12 hour PKof nevirapine showed a gender difference of an 18.9%Table 5 Linear regression models for square-root transformed Cmin and CmaxCmin CmaxVariables Beta 95% CI p-value Beta 95% CI p-valueAge (per 10 years) 0.02 (−0.07 - 0.11) 0.62 0.00 (−0.04 - 0.05) 0.95RaceWhite ReferenceBlack −0.16 (−0.35 - 0.03) 0.09 −0.06 (−0.16 - 0.04) 0.25Other −0.20 (−0.50 - 0.11) 0.20 0.01 (−0.15 - 0.17) 0.91Risk FactorIDU −0.21 (−0.45 - 0.04) 0.10 −0.10 (−0.23 - 0.02) 0.10Endemic country −0.08 (−0.26 - 0.10) 0.38 −0.07 (−0.16 - 0.02) 0.14Heterosexual contact 0.13 (−0.05 - 0.32) 0.16 0.07 (−0.03 - 0.16) 0.16Blood transfusion −0.08 (−0.38 - 0.22) 0.60 −0.08 (−0.23 - 0.07) 0.31Unknown −0.06 (−0.34 - 0.23) 0.69 0.01 (−0.14 - 0.15) 0.90Years since HIV diagnosis (per 10 years) 0.00 (−0.00 - 0.00) 0.84 −0.00 (−0.00 - 0.00) 0.53Baseline CD4 (per 100/μL) 0.02 (−0.02 - 0.06) 0.28 0.00 (−0.02 - 0.02) 0.97Baseline CD4 > 200/μL 0.07 (−0.11 - 0.24) 0.46 0.03 (−0.06 - 0.12) 0.51Current CD4 (per 100/μL) 0.04 ( 0.00 - 0.08) 0.03 0.01 (−0.01 - 0.03) 0.61Current CD4 > 200/μL 0.30 (−0.25 - 0.84) 0.28 0.16 (−0.12 - 0.44) 0.26Baseline VL (log10 copies/mL) −0.02 (−0.09 - 0.06) 0.64 −0.00 (−0.04 - 0.03) 0.81AIDS diagnosis 0.07 (−0.12 - 0.27) 0.46 0.06 (−0.04 - 0.16) 0.27Years on current regimen −0.01 (−0.05 - 0.03) 0.68 −0.00 (−0.02 - 0.02) 0.83Hepatitis B co-infection 0.22 (−0.34 - 0.78) 0.44 −0.04 (−0.33 - 0.24) 0.76Hepatitis C co-infection 0.18 (−0.07 - 0.44) 0.17 −0.10 (−0.23 - 0.03) 0.14Smoking StatusSmoker ReferencePrevious Smoker 0.02 (−0.27 - 0.31) 0.89 0.05 (−0.10 - 0.20) 0.49Never −0.13 (−0.31 - 0.06) 0.18 0.02 (−0.08 - 0.11) 0.70Hypertension 0.14 (−0.12 - 0.41) 0.28 0.02 (−0.12 - 0.15) 0.82Diabetes 0.02 (−0.43 - 0.47) 0.94 −0.05 (−0.28 - 0.18) 0.66Weight (per kg) 0.00 (−0.00 - 0.01) 0.36 0.00 (−0.00 - 0.00) 0.32BMI (per kg/m2) 0.00 (−0.01 - 0.02) 0.47 0.00 (−0.00 - 0.01) 0.64Menopausal (self-reported) 0.05 (−0.14 - 0.25) 0.59 0.03 (−0.07 - 0.14) 0.55IDU, injection drug use; VL, viral load; AIDS, acquired immunodeficiency syndrome; BMI, body mass index.Loutfy et al. BMC Infectious Diseases 2013, 13:256 Page 7 of 10http://www.biomedcentral.com/1471-2334/13/256lower AUC in males when corrected for body weight [26].In the same study, pregnant women had lower nevirapineexposure and this effect did not seem to be driven by bodyweight.Our data also adds to the literature on gender differ-ences in Cmax of current antiretroviral agents. These ob-servations should be interpreted with caution as thecollection of Cmax samples in this study was done at asingle standardized timepoint; therefore, if the Cmaxsampling time was slightly off from the real Tmax thenthe resulting Cmax observations would be interpreted aslower. In our study, atazanavir had the lowest ratios ofboth Cmin and Cmax versus historical reference values,but also the greatest observed inter-patient variability. Ingeneral, a higher degree of variability was noted for Cminas compared to Cmax values.Few studies have assessed intra-patient variability ofantiretroviral drug levels for either gender. Over our 3-week sampling period, we found higher intra-patientvariability in the PI-based regimens compared to theNNRTIs; a similar finding to the retrospective summaryprovided by Fabbiani and colleagues [47]. More specific-ally, unboosted atazanavir had the highest intra- andinter-patient CVs for Cmin and Cmax, whereas efavirenzand nevirapine had the lowest CVs for intra-patient vari-ability. This most likely reflects the longer half-life forboth nevirapine and efavirenz, compared to PIs. Despiteritonavir boosting for both, the intra-patient variabilityfor lopinavir Cmax was substantially lower than that ofatazanavir, which may reflect the absence of a food andgastric pH effects on lopinavir absorption as comparedto atazanavir absorption. In addition, lopinavir is co-formulated with ritonavir, thus ensuring simultaneouscoadministration of both drugs, whereas atazanavir ab-sorption may be impacted if ritonavir is not taken at thesame time for reasons such as patient choice (e.g., con-cerns of selective side effects of ritonavir) or forgetful-ness since ritonavir capsules require refrigeration. In ourstudy, inter-patient CV for Cmin and Cmax of boostedand unboosted atazanavir appeared to be lower than his-torical values from predominantly male populations,while intrapatient CV for Cmin of unboosted atazanavirappeared to be higher than historical data. For NNRTIs,observed intra- and inter-patient Cmin CVs of efavirenzand nevirapine appeared to be lower than historical con-trols. As such, the existence of sex-based differences inantiretroviral variability cannot be ruled out.Correlates of antiretroviral drug levels in women haveonly been investigated by few studies. Gibbons and col-leagues examined the potential for age-dependentchanges in lopinavir and efavirenz levels in female sub-jects in a retrospective analysis of therapeutic drug mon-itoring on non-pregnant women receiving eitherlopinavir/ritonavir 400 mg /100 mg twice daily orefavirenz 600 mg daily [48]. They found that women >50 years of age had significantly higher 8–16 hourefavirenz levels when compared to women < 40 years ofage (p=0.046). In our study, we found that Cmin ratio in-creased with CD4+ cell count and there was some indi-cation that it was lower among injection drug users.There were no statistically significant correlates of Cmax.Of note, there was no correlation between drug levelsand body weight or body mass index. The lack of statis-tical significance may be related to the attempts to makeour population homogenous.Our study has a number of limitations, most notablythe lack of a concurrent male control group whichwould have allowed real-time assessment of sex differ-ences in drug levels. The fact that historical control datawas used results in the inability to report on the demo-graphics of the controls including the true proportion ofcases that were male, ethnicity, weight, and co-infectionstatus. The restriction of our study to women on theirfirst cART regimen with virologic suppression to ensurehomogeneity likely contributed to the lack of rangeamongst our covariates, decreasing our ability to detectdifferences and associations. If higher concentrationswere associated with toxicity, then the women may haveswitched off the regimen or been inconsistently adherentand experienced viral failure and would not have beeneligible for this data set. The demand and time commit-ment for the participants was high and likely led to somedegree of selection bias of women who are committed totherapy and research. Also, there were small samplesizes for each drug dosing (e.g. only 4 participations tak-ing lopinavir/ritonavir 800 mg/100 mg OD and 8 takingnevirapine 400 mg OD) and for this reason it was diffi-cult to make conclusions regarding specific drugs anddrug dosing.ConclusionIn summary, our data adds to the growing literature onthe gender differences of antiretroviral drug levels. Ourstudy showed that the PIs and NNRTIs overall Cmin ra-tios were significantly higher in our HIV-positive femaleparticipants as compared to men (historical controls). Inparticular, we observed the highest Cmin for nevirapineand lopinavir. These latter observations add to the litera-ture by providing data on newer antiretroviral agents,and could explain nevirapine’s important gender-specificdrug toxicity. Our study was also able to study intra-and inter-patient variability for PIs and NNRTIs Cmin ra-tios and found significant variability particularly forunboosted and boosted atazanavir. This intra-patientvariability could have clinical implications with respectto toxicity and efficacy. These findings require furtherstudy to elucidate the mechanism and clinical conse-quences of these differences and results. It alsoLoutfy et al. BMC Infectious Diseases 2013, 13:256 Page 8 of 10http://www.biomedcentral.com/1471-2334/13/256emphasizes the importance of gender-specific analyseswhen investigating antiretroviral efficacy and toxicity.AbbreviationsAEs: Adverse events; AIDS: Acquired immune deficiency syndrome;ART: Antiretroviral therapy; AUC: Area under the curve; BID: Twice daily;BMI: Body mass index; cART: Combination antiretroviral therapy;CHUL: Centre Hospitalier Universitaire de Quebec; CI: Confidence interval;CIHR: Canadian Institutes of Health Research; Cmax: Maximum plasmaconcentration of the drug; Cmin: Minimum plasma concentration of the drug;CV: Coefficient variation; CVs: Coefficient variations; FRSQ: Fonds derecherche en santé du Québec; HIV: Human immunodeficiency virus;IDU: Injection drug user; IQR: Interquartile range; NNRTI: Non nucleosidereverse transcriptase inhibitor; NNRTIs: Non nucleoside reverse transcriptaseinhibitors; PGP: P-glycoprotein; PI: Protease inhibitor; PIs: Protease inhibitors;PK: Pharmacokinetics; QD: Once daily; REB: Research ethics board;TDM: Therapeutic drug monitoring; VL: Viral load.Competing interestsThere are no financial or non-financial competing interests related to thispaper and project.Authors’ contributionsMRL was the senior most responsible investigator for the project who hadstudy idea, wrote the protocol, sought funding and coordinated the project.MRL wrote the first and final drafts of the manuscript and is thecorresponding author. CJlP and ALT provided pharmacokinetic expertise tothe project and provided substantive edits to the manuscript. CJlP carriedout the PK testing of all the samples. SLB conducted the statistical analysesunder the direction of JMR, MRL and CJlP. SLB and JMR provided substantiveedits to the manuscript. SB assisted with referencing. SW, MBK, NP, BC, JBA,ARR, KG, JC, DH, DB, FMS, AdP, HL, ST contributed to the study idea andprotocol, acted as site investigators and enrolled participants for the study,and contributed to editing the manuscript. All authors reviewed themanuscript during preparation, provided critical feedback and approved thefinal manuscript.AcknowledgementsWe would like to thank the research coordinators, members of the SteeringCommittee and the participants of the study. This work was funded by theCanadian Institutes of Health Research (CIHR) (Grant # HBF – 90187) and theCIHR Canadian HIV Trials Network. Five investigators are also the recipients ofsalary support from the Canadian Institutes of Health Research (MRL), theOntario HIV Treatment Network (JMR, SLW, JBA), Fonds de la Recherche enSanté du Québec (MBK), and the Skate the Dream Fund from the TorontoWestern Hospital Foundation (JMR).Author details1Women’s College Research Institute, Women’s College Hospital, 790 BayStreet, Room 736, Toronto, Ontario M5G 2N8, Canada. 2Department ofMedicine, University of Toronto, Toronto, Ontario, Canada. 3University HealthNetwork, Toronto, Ontario, Canada. 4McGill University Health Centre,Montreal Chest Institute, Montreal, Quebec, Canada. 5Dalla Lana School ofPublic Health, University of Toronto, Toronto, Ontario, Canada. 6Departmentof Medicine, University of Toronto, Toronto, Ontario, Canada. 7Oak TreeClinic, BC Women’s Hospital and Health Centre, Vancouver, British Columbia,Canada. 8Department of Medicine, University of British Columbia, Vancouver,British Columbia, Canada. 9Department of Pharmacology and Therapeutics,University of British Columbia, Vancouver, British Columbia, Canada. 10OttawaHospital Research Institute, Toronto, Ontario, Canada. 11Department ofMedicine, University of Ottawa, Toronto, Ontario, Canada. 12SunnybrookHealth Sciences Centre, Toronto, Ontario, Canada. 13Department of Medicine,St. Michael’s Hospital, Toronto, Ontario, Canada. 14Windsor Regional HospitalMetropolitan Campus, Windsor, Ontario, Canada. 15Department of Medicine,Division of Infectious Diseases, Dalhousie University, Halifax, Nova Scotia,Canada. 16Victoria General Hospital, Halifax, Nova Scotia, Canada. 17Faculty ofMedicine, Division of Infectious Diseases, University of British Columbia,Vancouver, British Columbia, Canada. 18Department of Pathology andMolecular Medicine, McMaster University, Hamilton, Ontario, Canada.19Centre Hospitalier De L’Universite De Montreal, Hopital Notre-Dame,Montreal, Québec, Canada. 20University of Ottawa Health Services, Ottawa,Ontario, Canada. 21Centre Hospitalier Universitaire de Quebec – pavillonCHUL, Quebec, Quebec, Canada.Received: 8 March 2013 Accepted: 16 May 2013Published: 3 June 2013References1. 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Abstract 54.doi:10.1186/1471-2334-13-256Cite this article as: Loutfy et al.: Factors affecting antiretroviralpharmacokinetics in HIV-infected women with virologic suppression oncombination antiretroviral therapy: a cross-sectional study. BMCInfectious Diseases 2013 13:256.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitLoutfy et al. BMC Infectious Diseases 2013, 13:256 Page 10 of 10http://www.biomedcentral.com/1471-2334/13/256

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