Potent, durable antiretroviral salvage regimens for HIV-infected patients are needed. Generally, patients in whom prior protease inhibitor (PI)-containing regimens have failed (and who have developed genotypic resistance) have great difficulty in achieving optimal viral suppression and immunologic recovery with successive therapies. Recently, triple-PI regimens, which includes 2 active PIs along with ritonavir (RTV) as a pharmacokinetic-enhancing agent, have been examined for salvage therapy. These have included the combination of Kaletra (lopinavir [LPV]/RTV; Abbott Laboratories) with either amprenavir (APV), saquinavir (SQV), indinavir (IDV), or nelfinavir (NFV). 1–14 Pharmacokinetic studies with these triple-PI regimens have reported variable interactions. 1–8 Additionally, in subjects treated for 6–96 weeks, these triple-PI salvage regimens have shown mean or median 1.13–5.5 log decreases in HIV RNA and 88–248 cell/mm3 increases in CD4+ T cells/mm3.1,4,11,14
Recently, Furfine et al 15 proposed a combination of APV, SQV, and RTV for use in PI-experienced subjects. This regimen has the theoretical advantages of nonoverlapping APV and SQV resistance profiles and in vitro synergy. 15,16 Although this regimen may be used in clinical practice, no formal investigation of the pharmacokinetics of this regimen has been published to date. This study is the first designed to evaluate the pharmacokinetics, safety, and short-term efficacy of this triple-PI regimen.
A randomized, nonblinded investigation using real-time pharmacokinetic analyses was conducted in highly antiretroviral-experienced subjects treated with a regimen containing APV, SQV, and RTV. The primary objectives of this investigation were to quantify the change in SQV pharmacokinetics when combined with APV, to quantify the change in APV pharmacokinetics when combined with SQV, to establish the most appropriate dosing of an APV/SQV/RTV regimen should a drug interaction be evident, and to determine 24-week safety and immunologic and virologic response to this combination.
Subjects were screened from the University of North Carolina Infectious Diseases Clinic. HIV-1–infected male and female subjects ≥18 years of age, having plasma HIV-1 RNA concentrations >1000 copies/mL on at least 2 prior occasions, in whom at least 1 prior PI-containing regimen had failed were asked to participate. Informed consent was obtained from all subjects. Human experimentation guidelines of the US Department of Health and Human Services and those of the University of North Carolina at Chapel Hill were followed in the conduct of this clinical research study. A negative pregnancy test was required from women of childbearing potential. Subjects were on no other medications known to affect P-glycoprotein or cytochrome P450 enzyme activity.
HIV-1 RNA, CD4+ T-cell counts, and HIV-1 genotyping with virtual phenotyping were obtained at baseline. Genotyping with virtual phenotyping was performed by Virco Laboratory, Ltd. (Blanchardstown, Dublin, Ireland). Once the results of the genotyping and virtual phenotyping had been reviewed by the subject’s clinician, new nucleoside reverse transcriptase inhibitors (NRTIs) were prescribed and subjects were assigned by random number generator to receive either SQV 1000 mg + RTV 100 mg (SQV/RTV) twice daily (every 12 hours) or APV 600 mg + RTV 100 mg (APV/RTV) every 12 hours. Subjects were instructed to record all PI doses on a medication timing card.
As the pharmacokinetics for this combination of PIs were unknown at the time of this investigation, samples were assayed and pharmacokinetic analysis performed within 5 days of collection (real-time pharmacokinetics). Therapeutic drug monitoring for SQV, APV, and RTV was performed to adjust doses in the event of lower than expected plasma exposures. Doses of PIs were adjusted using linear pharmacokinetic principles based on the magnitude of change in drug exposure.
Blood samples were obtained for pharmacokinetic evaluation after 7–10 days of dual-PI therapy. After pharmacokinetic sampling, the subject was prescribed the 3rd protease inhibitor (SQV or APV). Blood samples were obtained for pharmacokinetic evaluation after 14 days of triple-PI therapy. Real-time pharmacokinetic analysis was completed within 5 days of this study visit. Antiretroviral doses were adjusted to achieve APV and SQV exposures similar to APV/RTV or SQV/RTV alone. Additional pharmacokinetic visits were conducted as needed after dose adjustments.
HIV-1 RNA, a chemistry panel, complete blood count with differential, liver function tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and alkaline phosphatase), fasting lipid panel and blood glucose, α-1-acid glycoprotein (AAG), and albumin were obtained at baseline, at each pharmacokinetics visit, and 8, 16, and 24 weeks after study entry. CD4+ T-cell counts were obtained at baseline and at 16 and 24 weeks.
APV (Agenerase; GlaxoSmithKline, Research Triangle Park, NC) 150-mg capsules and RTV (Norvir; Abbott Laboratories, Abbott Park, IL) 100-mg capsules were used throughout the study. SQV soft-gel capsules (SQV-SGC) (Fortovase; Roche Laboratories, Nutley, NJ) 200-mg capsules were used in 3 subjects at the initiation of the study. During this investigation, data became available demonstrating similar SQV exposure and decreased adverse effects with the SQV hard-gel capsule (SQV-HGC) (Invirase) formulation of SQV when combined with RTV. 17,18 At this time, all 3 subjects were switched to SQV-HGC 200 mg, and all newly enrolling subjects were prescribed this SQV formulation.
The evening prior to each 12-hour pharmacokinetic evaluation, study subjects were admitted to the General Clinical Research Center at UNC. Adherence was assessed by pill counts and medication administration records. The evening dose of PIs was observed, and the time of administration was recorded. After an overnight fast, the morning dose of PIs was observed and recorded, and blood samples were drawn at 0 hours (predose), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after dose administration for determination of APV, SQV, and RTV pharmacokinetics. A nonstandardized meal was allowed at least 2 hours after the morning dose. Whole blood was collected in ethylenediamine tetra-acetic acid Vacutainer tubes (Becton Dickinson; Franklin Lakes, NJ) and centrifuged at 2600 rpm at 4°C within 30 minutes of collection. Plasma was stored at −70°C until analysis. APV, SQV, and RTV concentrations were measured by the UNC Center for AIDS Research Clinical Pharmacology/Analytical Chemistry Core by a validated high-performance liquid chromatography/UV assay (lower limit of quantification = 25 ng/mL; inter- and intraday variability <9%) adapted from van Heeswijk et al. 19 Noncompartmental pharmacokinetic analysis was performed using WinNonLin Pro (V4.0.1; Pharsight, Mountain View, CA) software. Area under the concentration-time curve (AUC) was calculated using the linear-log trapezoidal rule.
All HIV-1 RNA assays were performed by the UNC Hospitals Virology Laboratory and the Center for AIDS Research Retrovirology Laboratory (Chapel Hill, NC). HIV-1 RNA was measured using the reverse transcriptase polymerase chain reaction Roche Amplicor assay (below limit of quantification <50 copies/mL). CD4+ T-cell counts were performed by the UNC Hospitals Flow Cytometry Laboratory (Chapel Hill, NC).
Adverse events were assessed by a questionnaire administered at each study visit. The AIDS Clinical Trials Group toxicity grading scale 20 was used for toxicity documentation. Subjects experiencing grade 3 or 4 toxicities were reported to the UNC Institutional Review Board and subsequently withdrawn from the study.
This study was originally powered to test whether the exposure of APV was lower when combined with SQV, and whether the exposure of SQV was lower when combined with APV. AUC for the dosing interval at steady state (AUC0–τ h · μg/mL) and concentration at the end of the dosing interval at steady-state (Cτ,ss ng/mL) were the exposure parameters used in these calculations. We estimated the geometric mean (95% CI) of AUC0–τ and Cτ,ss for APV (given as 600 mg with RTV 100 mg) to be 28.9 (21.1, 39.7) h · μg/mL and 1.49 (1.06, 2.08) μg/mL, respectively. 21 At the time of the study, no data were available for SQV 1000 mg/RTV 100 mg. The predicted geometric mean (95% CI) of Cτ,ss for SQV was 1.4 (0.4, 4.9) μg/mL based on interpolated calculations from data generated by Kilby et al. 22 Using a one-sided t test with α = 0.05 and power = 0.80, a sample size of 10 would allow detection of a 33% reduction in pharmacokinetic parameters. All statistical analyses were performed using SAS JMP 5.0 (SAS Institute, Inc., Cary, NC).
Due to the unanticipated multiple dosing combinations that were required during this study to find the most optimal regimen, and the subsequently small sample size within each dosing group, statistical analyses were not performed for comparisons between dosing regimens. Rather, geometric mean ratios (95% CI) are used for pharmacokinetic comparisons between dosing regimens, and summary 12-hour concentration-time data are provided in graphic form. Summaries of pharmacokinetic parameters and laboratory results are reported as median (range).
Eleven highly antiretroviral-experienced HIV-infected subjects (9 men, 2 women) were enrolled from August 2001 until May 2002. Subject demographics are listed in Table 1. These were highly antiretroviral-experienced subjects, previously receiving a median of 4.5 NRTIs, 1 NNRTI, and 3.5 PIs. Median (range) virtual phenotypes for the NNRTIs and PIs are listed in Table 1.
In addition to APV, SQV, and RTV, 9 subjects were also prescribed tenofovir with a combination of either didanosine (n = 3), lamivudine (n = 3), stavudine (n = 2), or abacavir (n = 1). One subject was prescribed abacavir/didanosine, and one other received zidovudine/lamivudine.
Figure 1 describes the dosing sequences of the enrolled subjects, defining the treatment arms A–F. Five subjects were randomly assigned to receive SQV 1000 mg/RTV 100 mg every 12 hours, whereas the remaining 6 were given APV 600 mg/RTV 100 mg every 12 hours. Pharmacokinetic analysis was performed after a median of 9 days on this therapy. The third PI was added to the subjects’ regimen, and pharmacokinetic analysis was repeated after 16 (13–25) days on triple-PI therapy. The 3 subjects who began the study taking SQV-SGC were switched to SQV-HGC after pharmacokinetic analysis while on treatment arm C.
On the dual-PI regimen, SQV and APV exposures were similar to previously published data. The AUC0–12h and Cτ,ss of SQV were 17.32 (6.32–25.84) h · μg/mL and 0.39 (0.08–0.47) μg/mL. The AUC0–12h and Cτ,ss of APV were 37.03 (17.13–61.24) h · μg/mL and 1.58 (0.62–3.95) μg/mL. Pharmacokinetic data are summarized in Table 2. When SQV was added to the APV/RTV regimen, there was minimal change in APV or RTV exposure. Geometric mean 95% CI ratios for APV AUC0–12h and Cτ,ss (comparing the triple-PI regimen to the dual PI regimen) were 1.01 (0.77, 1.33) and 1.31 (0.93, 1.84), respectively. However, the addition of APV to the SQV/RTV regimen resulted in significant decreases in SQV and RTV exposure. The geometric mean 95% CI ratios for SQV AUC0–12h and Cτ,ss (comparing the triple-PI regimen to the dual-PI regimen) were 0.21 (0.01, 0.45) and 0.36 (0.19, 0.68), respectively. The geometric mean ratios for RTV AUC0–12h and Cτ,ss were 0.19 (0.07, 0.51) and 0.24 (0.08, 0.70), respectively.
As SQV exposure was much less than expected in arm C, 3 strategies were further explored to correct this drug interaction. This experimental design was not prospectively planned but was performed by necessity due to the significant drug interaction identified early between APV and SQV/RTV. Linear pharmacokinetic principles were used to increase doses of SQV, RTV, or both. Subjects were assigned to receive an increase in SQV dose to 1400 mg every 12 hours; an increase in RTV dose to 200 mg every 12 hours; or both an increase in RTV dose to 200 mg every 12 hours and an increase in SQV dose to 1400 mg every 12 hours. Subjects taking study medications when concentrations of the original triple-PI regimen were deemed inferior were switched to a higher dose of SQV. Once this dosing strategy was deemed inferior, RTV doses were increased. Both SQV and RTV doses were increased in all subjects in the study, once the previous efforts were determined to result in inappropriate concentrations of SQV. Figure 2A–C are graphic representations of the pharmacokinetic interaction between these 3 PIs.
Increasing the SQV dose to 1400 mg twice daily (treatment D) did not correct for APV’s effects on SQV and RTV pharmacokinetics. In 3 subjects, SQV AUC0–12h and Cτ,ss were 3.94 (1.69 – 4.83) h · μg/mL and 0.08 (0.07 – 0.08) μg/mL. RTV AUC0–12h and Cτ,ss were 4.17 (2.79 – 5.66) h · μg/mL and 0.14 (0.04 – 0.20) μg/mL. APV pharmacokinetics remained unchanged.
Increasing the RTV dose to 200 mg every 12 hours (treatment E) increased SQV and RTV exposure but did not completely reverse APV’s effects. In 6 subjects, SQV AUC0–12h and Cτ,ss were 7.45 (2.65 – 12.57) h · μg/mL and 0.19 (0.07 – 0.48) μg/mL, respectively. RTV AUC0–12h and Cτ,ss were 16.50 (9.86 – 28.31) h · μg/mL and 0.31 (0.15 – 0.73) μg/mL, respectively. APV exposures increased slightly.
In 7 subjects, SQV doses were increased to 1400 mg every 12 hours and RTV doses were increased to 200 mg every 12 hours. With this regimen, geometric mean 95% CI ratios for SQV AUC0–12h and Cτ,ss (comparing the triple-PI regimen to the dual-PI regimen) were 0.62 (0.19, 2.00) and 0.88 (0.17, 4.56), respectively. Geometric mean 95% CI ratios for RTV AUC0–12h and Cτ,ss were 1.70 (0.57, 5.12) and 1.89 (0.41, 8.74), respectively. Geometric mean 95% CI ratios for APV AUC0–12h and Cτ,ss were 1.49 (0.74, 3.02) and 1.71 (0.61, 4.83), respectively. The high pill burden precluded any further increase in dosing; however, with this regimen, SQV and RTV exposures were similar to the SQV 1000 mg/RTV 100 mg twice-daily regimen.
To assess whether drug concentration changes were due to alterations in protein binding, AAG and albumin were measured at each visit. There was minimal change in the concentration of either protein throughout the study. Baseline, 8-week, and 24-week AAG concentrations were 103 (71 – 187), 121 (97 – 184), and 129 (71 – 187) mg/dL, respectively. Baseline, 8-week, and 24-week albumin concentrations were 4.1 (2.0 – 4.7), 4.0 (1.6 – 4.5), and 3.9 (3.2 – 4.3) g/dL, respectively.
Four subjects were withdrawn from the study due to poor adherence (<60% of prescribed doses taken). Appropriate steady-state concentrations may not have been achieved with this adherence pattern, thereby affecting pharmacokinetic data from these 4 patients. However, the doses given just prior to and during the pharmacokinetics visits were observed, and drug exposures in these individuals were not noticeably different from subjects with good adherence patterns. The remaining 7 subjects had >98% adherence (3 subjects missed no doses, 2 subjects missed 2 doses, and 2 subjects missed 7 doses).
HIV RNA and CD4+ T-cell count data were collected over 24 weeks. HIV RNA decreased by 1.32 (0.28 – 2.63) log copies/mL at 8 weeks (n = 10), 0.98 (0.13 – 2.69) log copies/mL at 16 weeks (n = 9), and 1.55 (0.21 – 2.88) log copies/mL at 24 weeks (n = 6). CD4+ T-lymphocyte counts increased 46 (−92 to 172) cells/mm3 at 16 weeks (n = 8) and 52 (−22 to 185) cells/mm3 at 24 weeks (n = 6).
All subjects experienced some degree of self-limiting grade 1 diarrhea, which improved within 2 weeks of triple-PI therapy. Six subjects had loose stools throughout the study controlled with either loperamide or diphenoxylate/atropine. Fasting blood glucose measures did not change over 24 weeks. Blood glucose at baseline was 91 (85 – 113) mg/dL and at 24 weeks was 98 (75 – 117) mg/dL. Baseline fasting triglyceride and cholesterol concentrations were 485 (41 – 1234) mg/dL and 241 (141 – 369) mg/dL. By week 24, fasting triglyceride and cholesterol concentrations were 720 (81 – 2305) mg/dL and 243 (153 – 351) mg/dL. Overall, triglycerides increased by 314 (40 – 1071) mg/dL, and cholesterol increased by 43 (12 – 110) mg/dL. One subject developed grade 2 liver toxicity at 16 weeks (aspartate aminotransferase and alanine aminotransferase were 4.3 and 2.7 times the upper limit of normal, respectively) and was removed from the study. This was not a unique event with this specific antiretroviral regimen, as the subject had a history of increasing liver function test results with exposure to other PIs.
During this study, 5 subjects discontinued therapy: 4 subjects were nonadherent and were either removed from the study or chose to withdraw, and 1 was withdrawn at 16 weeks due to grade 2 hepatotoxicity.
Using a combination of 3 PIs is one approach to treating highly antiretroviral-experienced patients. Triple-PI investigations using combinations of LPV/RTV and either APV, SQV, or IDV have reported variable drug exposures and variable virologic and immunologic responses. 1–12 The combination of APV, SQV, and RTV may have advantages over these combinations. HIV-1 isolates with resistance to APV have demonstrated hypersusceptibility to SQV. 15 Additionally, APV and SQV are synergistic when combined in vitro. 16
At the time of initiation of this investigation, no data were available on optimal every-12-hour dosing regimens for SQV/RTV. Based on compiled data from Roche Laboratories, we chose a regimen of SQV 1000 mg/RTV 100 mg every 12hours, which was estimated to provide C12h concentrations of approximately 1.5 μg/mL. Subsequently, an investigation by Kurowski et al 17 demonstrated that this dosing strategy provided mean (range) C12h SQV-HGC (Invirase) concentrations of 0.37 (0.07 – 2.54) μg/mL in 24 HIV-infected subjects. 17 Likewise, Veldkamp et al 18 demonstrated a median (interquartile range) C12h SQV-SGC (Fortovase) of 0.40 (0.28 – 0.80) in 6 HIV-infected subjects. 18 Our data with SQV/RTV are similar.
Previous in vitro data reported by Huang et al 23 have suggested that APV can induce the cytochrome P450 3A subfamily of drug-metabolizing enzymes. 23 Healthy volunteer studies have demonstrated this same induction effect of APV by reducing exposure of delavirdine. 24,25 As SQV and RTV are substrates for the cytochrome P450 3A enzymes, 26,27 we believe the reason for lowered SQV and RTV exposures when combined with APV is likely APV’s drug-metabolizing enzyme regulation. As illustrated in Figure 2C, this induction process decreased RTV exposures from a typical SQV/RTV regimen, to a typical APV/RTV regimen, which diminished the pharmacokinetic-enhancing effects of RTV on SQV. With the addition of APV, SQV AUCs declined an average of 82% and RTV AUCs declined an average of 74%. The primary effect was seen during first-pass metabolism, with maximum concentrations (Cmax) decreasing for both SQV and RTV. This is consistent with other data demonstrating RTV’s influence on the first-pass metabolism of SQV. 28
Increasing SQV dosing to 1400 mg every 12 hours for 14 days did not substantially increase SQV exposure. Increasing RTV dosing to 200 mg every 12 hours for 14 days resulted in an average 169% increase in SQV AUC and an average 477% increase in RTV AUCs over the original triple-PI regimen. However, the AUC for SQV was still 58% lower than what was seen with SQV/RTV administered alone.
Increasing SQV to 1400 mg and RTV to 200 mg every 12 hours resulted in an increase in SQV AUC of 195% and an increase in RTV AUC of 221%. Because these AUCs were only 26% (SQV) and 17% (RTV) lower than SQV/RTV administered alone, we believe this dosing strategy could be a reasonable approach when APV, SQV, and RTV are used together. However, a larger patient population is required to confirm these results.
Nine of the 11 subjects were concomitantly taking tenofovir. Previous reports have demonstrated tenofovir interactions with NRTIs and PIs. 29–33 In our subjects, it did not appear that tenofovir affected the pharmacokinetics of our PI regimen, although our numbers were too small for formal comparisons. However, preliminary data from a recently completed study evaluating the interaction between tenofovir and SQV has demonstrated no appreciable effects on SQV pharmacokinetics (personal communication, Andrew Hill, 2003).
Data on triple-PI regimens are varied and include combinations of LPV/RTV and APV, SQV, IDV, or NFV. 1–12 Most are prospective investigations in HIV-infected, treatment-experienced patients. 1–4,6–12 A decline in HIV RNA (−1.13 log to −5.5 log) and increase in CD4+ counts (+88 to +248 cell/mm3) were seen in all studies that evaluated efficacy. 1,4,11,14 Subjects enrolled in this study were also heavily antiretroviral experienced, receiving a median of 4.5 (2 – 5) NRTIs, 1 (0 – 2) NNRTIs, and 3.5 (1 – 6) PIs prior to study enrollment. Based on virtual phenotype, these subjects also had high-level resistance: the fold increase of IC50 for NRTIs, NNRTIs, and PIs ranged from 0.8–55.7, from 1.1–153.2, and from 0.8–73.7, respectively. However, using the APV/SQV/RTV combination of PIs (along with 2 nucleoside/tide analogue RT inhibitors), we also observed positive virologic responses. HIV RNA declined a median of 1.55 log copies/mL and CD4+ T-cell counts increased 52 cells/mm3 at 24 weeks.
This patient population is most comparable to that studied by Baldini et al. 1 These investigators evaluated the combination of LPV/RTV and APV in 22 highly experienced subjects. Subjects received standard doses of LPV/RTV and 600 mg APV every 12 hours for 24 weeks with week 2 limited pharmacokinetic sampling. APV concentrations were 18 – 37% lower than reference controls and LPV exposures were as expected. These subjects experienced a mean (SD) decline in HIV RNA of 1.13 (1.30) log and an increase in CD4+ counts of +88 (87) cells/mm3 at 24 weeks. 1 Fifty percent of these patients had grade 3–4 laboratory abnormalities (mostly hypertriglyceridemia), and 27% discontinued treatment due to an adverse event. In this small cohort, HIV RNA and CD4+ responses were similar, with lower toxicity rates and treatment discontinuations due to adverse events. However, due to the small sample size, these results should be confirmed in a larger cohort of individuals.
The majority of adverse effects from the combination of APV/SQV/RTV in this investigation were mild and self-limiting. None of the subjects who discontinued due to nonadherence reported significant adverse events. Ongoing gastrointestinal disturbances were successfully treated with pharmacologic measures. Increases in triglycerides and cholesterol, as expected, were elevated with PI administration; however, they did not appear directly related to increasing RTV dosing from 100 mg to 200 mg twice daily. Three of the 4 subjects with triglyceride elevations at 24 weeks had elevated triglycerides at baseline, and one of these subjects had a large (1071-mg/dL) increase at 24 weeks. However, this subject was successfully treated with fenofibrate and pravastatin and remains on this regimen (now at 120 weeks of therapy).
The greatest limitation to this regimen is adherence to the large pill burden. Presently, the pill burden for this combination (excluding the concomitant NRTIs) is 13 (4 capsules of APV, 7 capsules of SQV, 2 capsules of RTV) taken twice daily. Most of our subjects were highly antiretroviral-experienced patients familiar with taking large numbers of pills and motivated to take their antiretroviral regimens consistently. However, even in this cohort, 4 of 11 subjects were removed from the study due to poor adherence as a result of the pill burden.
New formulations of APV and SQV are either available or being developed that might decrease the pill burden of this regimen. Fosamprenavir (GW433908, GlaxoSmithKline) is an APV prodrug that was approved by the Food and Drug Administration in October of 2003. It can be given as one 700-mg capsule with 100 mg of RTV twice daily and achieve similar or higher exposures to the original formulation given 600 mg every 12 hours with RTV 100 mg every 12 hours. Additionally, a 500-mg tablet of SQV is currently being developed by Roche Pharmaceuticals that may provide even further decrease in pill burden. Preliminary data from a pharmacokinetic investigation suggest that a regimen of SQV 1000 mg twice daily may be combined favorably with fosamprenavir 700 mg twice daily and RTV 200 mg twice daily. 34 However, no clinical data are yet available.
In conclusion, this is the first study to investigate the pharmacokinetics and preliminary virologic response to HIV-infected patients treated with the PI combination of APV/SQV/RTV. Due to the effects of APV on drug-metabolizing enzymes, SQV and RTV doses must be increased to achieve SQV exposure similar to that of the commonly used SQV 1000 mg/ RTV 100 mg every-12-hour regimen. Based on these data in a small number of individuals, the combination of APV 600 mg/SQV 1400 mg/RTV 200 mg every 12 hours may be a viable regimen in a highly antiretroviral-experienced patient population, with limited adverse effects. A larger investigation of this promising combination using the new formulations of APV and SQV is warranted.
The authors thank the subjects for their participation in this investigation, and the support of the UNC GCRC staff.
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