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Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive,… Julio, Montaner S; Schutz, Malte; Schwartz, Robert; Jayaweera, Dushyantha T; Burnside, Alfred F; Walmsley, Sharon; Saag, Michael S May 10, 2006

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ralJournal of the International AIDS ssBioMed CentSocietyOpen AcceResearchEfficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected PatientsMontaner SG Julio*1, Malte Schutz2, Robert Schwartz3, Dushyantha T Jayaweera4, Alfred F Burnside5, Sharon Walmsley6 and Michael S Saag7Address: 1St Paul's Hospital, University of British Columbia, Vancouver, BC, Canada, 2Roche Laboratories, Inc, Nutley, New Jersey, 3Associates in Research, Fort Myers, Florida, 4University of Miami School of Medicine, Miami, Florida, 5Burnside Clinic, Columbia, South Carolina, 6Toronto Hospital, Toronto, Canada and 7University of Alabama at BirminghamEmail: Montaner SG Julio* - jmontaner@cfenet.ubc.ca* Corresponding author    AbstractContext: Once-daily HIV treatment regimens are being used in clinical practice with the objectiveof improving patient acceptance and adherence.Objective: To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavircombination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2nucleoside analogs twice daily.Setting: Twenty-six centers in the United States, Canada, and Puerto Rico.Patients: A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week,phase 3, open-label, randomized study.Main Outcome Measure: Proportion of patients with HIV-RNA levels < 50 copies/mL. Thepharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients.Results: In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) ofpatients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNAsuppression < 50 copies/mL (P = .5392, 95% 1-sided confidence interval [CI] = -33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P =.5015, 95% 1-sided CI = -33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/microliters(mcL), in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P =.058). Both regimens were reasonably well tolerated, although more gastrointestinal adverseevents were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patientsshowed an observed median Cmin at 24 hours of 429 ng/mL (range, 681750 ng/mL).Conclusion: Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in thePublished: 10 May 2006Journal of the International AIDS Society 2006, 8:36This article is available from: http://www.jiasociety.org/content/8/2/36Page 1 of 12(page number not for citation purposes)saquinavir-SGC/ritonavir arm of the study.Journal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36IntroductionThe introduction of highly active antiretroviral therapy(HAART) has produced dramatic reductions in morbidityand mortality rates associated with HIV-1 infection in theUnited States.[1,2] In clinical trials, HAART has reducedplasma HIV-1 RNA levels to less than 400 copies/mL in60% to 90% of patients.[3] Strict adherence to HAART isnecessary to prevent viral replication and the emergenceof drug-resistant viruses, which can compromise the finaltherapeutic benefit.[4,5] Treatment regimens withimproved dosing schedules, such as once-daily dosing, arelikely to improve patient acceptance and adherence.[6]Furthermore, once-daily dosing of HAART may be partic-ularly beneficial in the implementation of directlyobserved therapy (DOT) in prisons, at needle-exchangesites, and in drug rehabilitation programs.[4]To date, 6 antiretroviral (ARV) agents, efavirenz, tenofo-vir, didanosine, lamivudine, coformulated lamivudine/abacavir, atazanavir and amprenavir boosted with ritona-vir are approved for once-daily dosing by the US Food andDrug Administration (FDA). However, in addition tothese drugs, there are several agents such as nevirapineand other boosted protease inhibitors (PIs) that are beingused once daily in clinical practice based on their halflives. The availability of a wide choice of once-daily treat-ment regimens has made it easier for HIV-infectedpatients to find an optimal therapy that suits their life-style. While efavirenz appears to be an ideal once-dailytreatment option due to its potency and convenience witha low pill burden,[7] adverse events, in particular relatingto the central nervous system, have been reported follow-ing administration,[8] which may potentially limit its usein some HIV-infected patients. Additionally, efavirenzmay not be appropriate in some settings because it mayhave teratogenic effects.[8]Ritonavir-boosted PI regimens are widely used in clinicalpractice,[9,10] because several boosted PI combinationshave pharmacokinetic profiles that support once-dailydosing.[11] These include saquinavir/ritonavir,[12]amprenavir/ritonavir,[13] fosamprenavir/ritonavir,[14]lopinavir/ritonavir [15] and atazanavir/ritonavir.[16] Ininitial studies, positive pharmacokinetic and efficacy datahave been observed with the use of once-daily saquinavir/ritonavir in PI-naive and experienced individuals.[12,17]Therefore, to further investigate the saquinavir/ritonavirboosted PI combination as a potential once-daily treat-ment regimen, we evaluated the efficacy and safety ofsaquinavir-soft-gelatin capsule (SGC)/ritonavir 1600 mg/100 mg vs efavirenz 600 mg in a prospective, randomized,multicenter clinical trial. Both treatment regimens wereadministered once daily in addition to 2 nucleosidenaive, HIV-infected individuals. As part of this clinicalstudy, the pharmacokinetic profile of saquinavir-SGC wasassessed in a subset of patients.Materials and methodsStudy DesignThis was a phase 3, open-label, randomized, multicenterstudy conducted at 26 centers in the United States, Can-ada, and Puerto Rico. Antiretroviral-naive, HIV-infectedadults were randomized to receive either saquinavir-SGC/ritonavir (1600 mg/100 mg, 9 pills) or efavirenz (600 mg,3 pills) once daily, both in combination with 2 NRTIstwice daily. An interim analysis was planned at week 24,with a follow-up extension to week 48. Once patientsreached 48 weeks, they had the option of continuing inthe study until a common study closure (CSC) date or ofwithdrawing at that time. The CSC date was the date onwhich the last randomized patient reached 48 weeks oftreatment.The NRTIs allowed in the study included the followingagents: zidovudine (AZT, Retrovir), lamivudine (3TC, Epi-vir), 3TC/AZT (Combivir), stavudine (d4T, Zerit), or dida-nosine (ddI, Videx). The NRTIs were selected by theinvestigators following consultation with the study partic-ipants, with the exception of didanosine, which wasdosed twice daily according to the FDA approval status atthe time this study was conducted. Patients were rand-omized via stratification of the screening plasma HIV-RNA value (500075,000 copies/mL vs > 75,000 copies/mL). Saquinavir-SGC and ritonavir were to be taken at thesame time and with food. The study was designed andmonitored in accordance with Good Clinical Practices.Prior approval was obtained from institutional reviewboards/local ethics committees of the participating cent-ers and written informed consent was obtained from allstudy participants.PatientsThe defined study population consisted of male or female(nonpregnant, nonnursing) adults (18 years or older),with HIV-RNA values  5000 copies/mL and CD4+ cellcounts  75 cells/mcL. All patients were ARV-naive (nomore than 2 weeks of previous ARV therapy since HIVdiagnosis). Patients with significant laboratory abnormal-ities, active hepatitis B or hepatitis C, severe hepaticimpairment, or malignancy requiring chemotherapy orradiation therapy were excluded from the study.Study PopulationsAll efficacy analyses were performed on the primaryintent-to-treat (ITT) and on-treatment (OT) populations.The primary ITT population included all patients whoPage 2 of 12(page number not for citation purposes)reverse transcriptase inhibitors (NRTIs) (twice daily) aspart of combination HAART therapy regimens to ARV-received at least 1 dose of study drug after randomizationand had at least 1 efficacy evaluation. The OT populationJournal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36included those patients in the study who had an observa-tional value for all efficacy variables and laboratory meas-urements, at that particular timepoint in the study. Thesafety-evaluable population included all randomizedpatients who received at least 1 dose of study medicationand had at least 1 postbaseline safety assessment.Efficacy and Safety MeasuresThe primary efficacy variable was the proportion ofpatients with plasma HIV-RNA values < 50 copies/mLusing the Ultra-Sensitive assay (Roche Diagnostics), atweeks 24 and 48. Secondary efficacy analyses included thechange from baseline in CD4+ cell counts. Primary andsecondary variables were assessed at baseline (week 0),every 4 weeks until week 24, and every 8 weeks until week48, or at study discontinuation.Adverse events were graded by intensity, and their rela-tionship to the study medications was assessed. Fastinglipid profile was also assessed. Laboratory abnormalitieswere graded by severity. Marked laboratory shifts weredefined as a  3 grade shift from baseline (grade 03 or 4and grade 14).Pharmacokinetic SubanalysisA subanalysis was performed to assess the pharmacoki-netic profile of saquinavir-SGC in a subset of randomlyselected patients. Intensive pharmacokinetic assessmentswere performed on patients from 2 preselected study cent-ers after the completion of 4 weeks of therapy. Followinga standard breakfast, saquinavir-SGC/ritonavir 1600 mg/100 mg was administered with 2 NRTIs. Samples for anal-ysis of saquinavir-SGC (7 mL) were taken predosing (hour0) and at 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose. Atweek 4, single trough plasma concentrations of saquina-vir-SGC were also determined in a larger group ofpatients. For patients who took their dose in the morning,single samples were taken before their next morning dose(approximately 24 hours later) and for those who tooktheir dose in the evening, samples were taken at least 12hours after the previous dose.Pharmacokinetic AnalysisSaquinavir-SGC plasma concentration was assayed usinga validated SCIEX API liquid chromatography extractionmethod with a mass spectrophotometric (LC-MS) detec-tion system. The method was validated for a range of53000 ng/mL. For patients who underwent intensivepharmacokinetic evaluation, the variables assessed werearea under the curve over 24 hours (AUC024 h), maximumplasma concentration (Cmax) and observed trough plasmaconcentration (Cmin). Cmax and Cmin were read directlyfrom the observed data. The AUC data were obtained byIn patients with a single trough plasma sample, Cmin at 24hours (C24 h) was the pharmacokinetic variable of interestand saquinavir-SGC C24 h was mathematically extrapo-lated to reflect 24-hour levels, assuming an eliminationhalf-life of 56 hours.[18] The equation C1 = C0e(-kel • t)was used to calculate the saquinavir-SGC C24 h extrapo-lated levels where: C1 = concentration extrapolated at 24hours; C0 = observed concentration; kel = the eliminationrate constant for the drug (kel = 0.693/t 1/2); t = differ-ence in time between C1 and C0; and t 1/2 is defined as thehalf-life of the drug.Descriptive statistics for the pharmacokinetic parametersof saquinavir-SGC were summarized to compare themwith historical values obtained with the licensed dose ofsaquinavir-SGC (1200 mg 3 times daily [TID]).Statistical AnalysesThis study was designed to compare the efficacy of once-daily dosing of saquinavir-SGC/ritonavir 1600 mg/100mg vs efavirenz 600 mg at weeks 24 and 48, using the pro-portion of patients with HIV-RNA values < 50 copies/mL(response rate). Group differences in the proportion ofpatients with HIV-RNA levels < 50 copies/mL were ana-lyzed using a noninferiority test. The Farrington-Manningmethod for testing noninferiority was used to derive P val-ues and to construct 1-sided 95% confidence intervals(CI) of the rate difference.[19] If the limit of the 95% 1-sided CI of the difference rate was greater than -20%, thennoninferiority was concluded. Mean changes from base-line in CD4+ cell counts were analyzed using an analysisof variance (ANOVA) model. Safety variables were sum-marized using descriptive statistics for the entire studyperiod up to the CSC date. Fisher's exact test was used tostatistically compare the incidence of adverse events inboth treatment groups.ResultsPatients and Study CourseFrom July 1999 to October 2001, 269 patients werescreened and 171 were randomized to treatment (Figure1). Six patients withdrew from the primary ITT populationbefore receiving study medication, giving a total of 165patients who received study drug. Of these, 13 patientswere excluded because no postrandomization on-drugefficacy evaluation was available. The resulting primaryITT population included 75 patients in the saquinavir-SGC/ritonavir group and 77 patients in the efavirenzgroup. Of the primary ITT population, 108 patients com-pleted all 48 weeks of the study (51 in the saquinavir-SGC/ritonavir group and 57 in the efavirenz group). Atweek 48, the OT population consisted of 110 patients: 52and 58 patients in the saquinavir-SGC/ritonavir and efa-Page 3 of 12(page number not for citation purposes)noncompartmental analysis. virenz arms, respectively. The safety population consistedof 161 randomized patients: 81 and 80 patients in theJournal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36saquinavir-SGC/ritonavir and efavirenz group, respec-tively.At the CSC date, 51/152 (34%) patients had withdrawnfrom the primary ITT population: 28/75 (37%) patientsfrom the saquinavir-SGC/ritonavir group and 23/77(30%) patients from the efavirenz group (Figure 1). Ofthese, 18 patients withdrew due to failure to return forreassessment (8 in the saquinavir-SGC/ritonavir arm and10 in the efavirenz arm), 13 patients refused treatment/withdrew consent (11 in the saquinavir-SGC/ritonavirarm and 2 in the efavirenz arm), and 12 withdrew due toadverse events (8 in the saquinavir-SGC/ritonavir arm and4 in the efavirenz arm). The demographic and baselinecharacteristics of the patients in the saquinavir-SGC/riton-avir and efavirenz arms were similar, with respect to gen-der, age, race, baseline HIV-RNA levels and CD4+ counts(Table 1). The majority (73%) of patients in both armswas male, 47% were black, and the age range was 1961years (median, 36 years).EfficacyPlasma HIV RNA Responsesaquinavir-SGC/ritonavir and efavirenz groups, respec-tively, had HIV-RNA values < 50 copies/mL (P = .5255,95% 1-sided CI = -32.0%). At the 48-week time-point, therespective values were 51% (38/75) and 71% (55/77) (P= .5392, 95% 1-sided CI = -33.5%).In the OT population, at week 24, 82% (46/56) and 90%(61/68) of patients had HIV-RNA levels < 50 copies/mL inthe saquinavir-SGC/ritonavir and efavirenz groups,respectively (P = .0374, 95% 1-sided CI = -19.05%). Byweek 48, 73% (38/52) and 93% (54/58) of patients hadHIV-RNA levels < 50 copies/mL, respectively (P = .5015,95% 1-sided CI = -33.3%).Changes in CD4+ Cell CountsAt week 24, the mean increase in CD4+ cell counts was170 cells/mcL in the saquinavir-SGC/ritonavir arm com-pared with 143 cells/mcL in the efavirenz arm (P = .344;OT population). At the 48-week study endpoint, this hadincreased to 239 cells/mcL and 204 cells/mcL, in thesaquinavir-SGC/ritonavir and efavirenz groups, respec-tively (P = .058; OT population).Study design and completion statusFigure 1Study design and completion status. ITT = intent to treatEfavrienz arm, n = 85Saquinavir soft gelatin capsule/ritonavir arm, n = 86*Up to the common study closure date (October 02, 2001 ± 2 weeks).Randomizedn = 171Withdrew priorto receiving study drugn = 4Withdrew prior toreceived study drungn = 2Efficacy evaluationnot availablen = 6Withdrew from study*(n = 23)Refused treatment n = 2Failure to return n = 10Adverse event n = 4Laboratory toxicity n = 3Insufficient therapeutic response n = 2Other n = 2Efficacy evaluationnot availablen = 7Withdrew from study*(n = 28)Refused treatment n = 11Failure to return n = 8Adverse event n = 8Laboratory toxicity n = 0Insufficient therapeutic response n = 1Other n = 0Received treatmentas allocatedn = 82Received treatmentas allocatedn = 83Took medication and hadan efficacy evaluation(Primary ITT population)n = 75Took medication and hadan efficacy evaluation(Primary ITT population)n = 77Completed 48-week studyn = 51Completed 48-week studyn = 57Page 4 of 12(page number not for citation purposes)As shown in Figure 2, in the primary ITT population atweek 24, 63% (47/75) and 83% (64/77) of patients in theJournal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36SafetyOverall, adverse events were reported by 98% and 94% ofpatients in the saquinavir-SGC/ritonavir and efavirenzgroups, respectively. The majority of adverse events weremild or moderate in intensity. During the entire studyperiod, 11% (18/161) of patients in the safety populationdiscontinued treatment due to adverse events. In thesaquinavir-SGC/ritonavir group 15% (12/81) of patientsto adverse events. The most commonly reported adverseevents leading to withdrawal in the saquinavir-SGC/riton-avir group were gastrointestinal in nature, including nau-sea and vomiting. In contrast, weight loss, peripheralneuropathy and abnormal dreams were the reportedadverse events leading to withdrawal in the efavirenzgroup.Table 1: Summary of Patient Characteristics at Baseline (Primary Intent-to-Treat Population)Characteristic Saquinavir-SGC 1600 mg + ritonavir 100 mg, Once Daily (n = 75)Efavirenz 600 mg Once Daily (n = 77)Male n (%) 53 (71) 58 (75)Female n (%) 22 (29) 19 (25)Race n (%)White 28 (37) 29 (38)Black 34 (45) 38 (49)Hispanic 6 (8) 8 (10)Other 7 (9) 2 (3)Age (y); mean ± SD(range) 37.2 ± 9.7 (2061) 37.2 ± 9.9 (1961)Weight (kg); mean ± SD (range) 78.0 ± 16.5 (52126) 75.4 ± 15.0 (44136)Plasma HIV RNA (log10 copies/mL); mean ± SD (range)4.8 ± 0.6 (3.346.49) 4.7 ± 0.5 (3.515.66)CD4+ cell count (cells/mcL); mean ± SD (range) 372 ± 190 (751025) 343 ± 180 (80900)Nucleoside reverse transcriptase inhibitor combination therapy; n (%)3TC-AZT 47 (63) 52 (68)3TC-d4T 27 (36) 22 (29)3TC-ddI 0 2 (3)AZT-ddI 1 (1) 0d4T-ddI 0 1 (1)Stratification (HIV RNA); n (%) copies/mL 500075,000 39 (52) 43 (56)> 75,000 copies/mL 36 (48) 34 (44)SGC = soft gelatin capsule; SD = standard deviation; 3TC = lamivudine; AZT = zidovudine; d4T = stavudine; ddI = didanosine.Page 5 of 12(page number not for citation purposes)experienced adverse events that led to withdrawal and 8%(6/80) of patients withdrew from the efavirenz group dueAdverse events of moderate, severe or life-threateningintensity that were considered possibly or probablyJournal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36related to study medication occurring in 2% or more ofpatients are shown in Table 2 . Overall, 42% (34/81) and29% (23/80) of patients in the saquinavir-SGC/ritonavirand efavirenz groups, respectively, reported at least 1adverse event of moderate, severe, or life-threateningintensity considered possibly or probably related to studymedication. Among adverse events, the rates of nauseadiffered significantly among treatment groups (Table 2).In total, 15 patients (7 [8.6%] and 8 [10.0%] patients inthe saquinavir-SGC/ritonavir and efavirenz groups,respectively) reported at least 1 serious adverse event,none of which were considered to be related to studymedication. One patient in the saquinavir-SGC/ritonavirgroup died due to myocardial infarction, which again wasnot considered to be related to study medication.Laboratory VariablesOverall, laboratory grade shifts in hematology and chem-istry values were similar in both treatment groups. Grade3/4 total cholesterol laboratory shifts were reported in 3patients in the saquinavir-SGC/ritonavir group comparedwith 7 patients in the efavirenz group. Mean triglycerideand total cholesterol levels assessed throughout the 48-week study period are presented in Figure 3. At weeks 24saquinavir-SGC/ritonavir group, compared with 27.0 mg/dL and 71.4 mg/dL, respectively, in the efavirenz group.The differences between groups were not statistically sig-nificant at weeks 24 and 48. Mean changes in total choles-terol levels were comparable between the 2 treatmentarms throughout the 48-week study period. Mean changesin high-density lipoprotein cholesterol at weeks 24 and 48were 7.9 mg/dL and 8.7 mg/dL, respectively, in thesaquinavir-SGC/ritonavir group compared with 9.3 mg/dL and 12.1 mg/dL, respectively, in the efavirenz group.PharmacokineticsOf 72 patients who were enrolled in the pharmacokineticsub-analysis, 6 underwent intensive pharmacokineticevaluation. Sixty-five patients had single plasma samplestaken at week 4 and data from 44 patients were suitablefor evaluation of trough concentrations (data from theremaining 21 could not be extrapolated because the sam-ples from 11 patients were taken less than 12 hours afterthe previous dose and the remaining 10 patients werenoncompliant). Furthermore, of the 6 patients includedin the intensive pharmacokinetic analysis, 1 patient wasnoncompliant and, therefore, not included in the single-trough evaluable cohort of patients. The single-troughevaluable cohort, therefore, consisted of 49 patients (5Percentage of patients treated with either saquinavir-soft gelatin capsule/ritonavir or efavirenz both once-daily in combination with 2 nucleoside revers  transcriptase inhibitors, with undetectable HIV-RNA levels (< 50 copies/mL), as detected by the Ul ra-Sensitive ssayFigure 2Percentage of patients treated with either saquinavir-soft gelatin capsule/ritonavir or efavirenz both once-daily in combination with 2 nucleoside reverse transcriptase inhibitors, with undetectable HIV-RNA levels (< 50 copies/mL), as detected by the Ultra-Sensitive assay. ITT = intent to treat; OT = on treatment1008060402000 4 8 12 16 20 24 32Time (Weeks)40 48HIV RNA , 50 Copies/mL(% Patients)Saquinavir soft gelatincapsule/ritonavir (ITT)Saquinavir soft gelatincapsule/ritonavir (OT)Efavirenz (ITT)Efavirenz (OT)Page 6 of 12(page number not for citation purposes)and 48, mean changes in triglyceride values from baselinewere 29.4 mg/dL and 51.2 mg/dL, respectively, in thepatients with intensive pharmacokinetics and 44 with sin-gle pharmacokinetic evaluations).Journal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36Page 7 of 12(page number not for citation purposes)Table 2: Clinical Adverse Events Considered to Be at Least Possibly or Probably Related to Treatment, at Least of Moderate, Severe or Life-Threatening Intensity, and Occurring in  2% of Patients in the Safety PopulationAdverse Event (ordered by body system) Saquinavir-SGC 1600 mg + ritonavir 100 mg, Once Daily (n = 81)Efavirenz 600 mg Once Daily (n = 80)n (%) n (%)Gastrointestinal disordersNausea* 18 (22.2) 3 (3.8)Vomiting NOS 5 (6.2) 0Diarrhea NOS 4 (4.9) 4 (5.0)Abdominal pain NOS 2 (2.5) 0Diarrhea aggravated 2 (2.5) 0Esophageal reflux 2 (2.5) 0General disordersFatigue 2 (2.5) 4 (5.0)Dizziness (excluding vertigo) 1 (1.2) 4 (5.0)Skin and subcutaneous tissue disordersDermatitis NOS 1 (1.2) 5 (6.3)Metabolic and nutritional disordersAppetite decreased 3 (3.7) 1 (1.3)Neurologic disordersHeadache NOS 2 (2.5) 2 (2.5)Insomnia 1 (1.2) 2 (2.5)Weakness 2 (2.5) 0Psychiatric disordersDepression NOS 2 (2.5) 1 (1.3)Anxiety 1 (1.2) 2 (2.5)Abnormal dreams 0 2 (2.5)Vascular disordersHypertension NOS 0 2 (2.5)SGC = soft gelatin capsule; NOS = not otherwise specified.*P = .0004; Fisher's exact test.Journal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36Intensive Pharmacokinetic Analysis at 4 WeeksThe intensive pharmacokinetic profile of the 6 unselectedpatients evaluated at 9 time points over 24 hours is shownin Figure 4. The median observed Cmin at 24 hours, Cmaxand AUC024 for these 6 patients were 429 ng/mL (range,681750 ng/mL), 6435 ng/mL (range, 172013,400 ng/Mean levels of triglycerides and total cholesterol in the safety population of patients treated with either saquinavir-soft gelatin capsule/ritonavi  or efavirenz both once daily in combination with 2 nucle side revers  transcriptase inhibitorsFigur  3Mean levels of triglycerides and total cholesterol in the safety population of patients treated with either saquinavir-soft gelatin capsule/ritonavir or efavirenz both once daily in combination with 2 nucleoside reverse transcriptase inhibitors.2502001501005000 4 8 12 16 20 24Time (Weeks)mg/dL32 40 48Triglycerides Saquinavir soft gelatincapsule/ritonavirTotal cholesterolSaquinavir soft gelatincapsule/ritonavirTriglyceridesEfavirenzTotal cholesterolEfavirenzIntensive pharmacokinetic profile of 6 patients at week 4Figure 41000001000010001001000 4 8 12EC50 for SaquinavirTime (Hours)Saquinavir Soft Gelatin CapsuleConcentration (ng/mL)16 20 24Page 8 of 12(page number not for citation purposes)Intensive pharmacokinetic profile of 6 patients at week 4. EC50 = concentration for 50% maximal effect.Journal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36mL), and 66,920 ng.h/mL (range, 10,542137,563 ng.h/mL), respectively.Saquinavir-SGC Trough Levels at Week 4The median saquinavir-SGC C24 h extrapolated level atweek 4 for all evaluable patients (n = 49) was 376 ng/mL(range, 2.55709 ng/mL). Eight patients had saquinavir-SGC C24 h extrapolated levels under the in vivo concentra-tion for half-maximal effect (EC50) value of 50 ng/mL(range, 2.545.2 ng/mL).[20] Despite this, these patientshad sustained HIV viral load suppression up to week 24.There was no significant correlation between saquinavir-SGC Cmin values and the reduction in plasma HIV RNAvalues from baseline to week 48.DiscussionThis 48-week study compared the efficacy and safety ofthe once-daily HIV treatment regimens, includingsaquinavir-SGC/ritonavir 1600 mg/100 mg, to that of efa-virenz 600 mg. The primary ITT analysis showed that ahigher proportion of patients in the efavirenz-treatedgroup achieved HIV-RNA levels < 50 copies/mL comparedwith the saquinavir-SGC/ritonavir-treated group. Morepatients withdrew from randomized treatment due to gas-trointestinal disorders in the saquinavir-SGC/ritonavirarm. The lower virologic response rate observed in thesaquinavir-SGC/ritonavir arm in the ITT population waspredominately due to the high rate of discontinuations,with 37% of patients withdrawing from the saquinavir/ritonavir arm, compared with 30% from the efavirenzarm. These withdrawals were related to gastrointestinalside effects, and possibly higher pill counts (patients tak-ing saquinavir-SGC/ritonavir had to take 9 capsules at 1time compared with 3 efavirenz capsules, together withthe background NRTIs). This study included a high per-centage of African-American patients and no specificadherence intervention was provided to overcome the dif-ference in pill burden in the 2 treatment arms.A previous comparative randomized trial of the boostedPI saquinavir-SGC/ritonavir has also shown lower viro-logic response rates, which have been attributed to differ-ences in study withdrawal rates as a result ofgastrointestinal toxicities in the saquinavir-SGC studyarms.[21] In the MaxCmin 2 study, which comparedtwice-daily saquinavir-SGC/ritonavir with lopinavir/ritonavir, comparable viral suppression was demonstratedin the OT analyses; however, the difference in study with-drawal rates due to gastrointestinal toxicity in the saquina-vir-SGC/ritonavir arm led to a lower overall response inthe ITT analyses.[21] The gastrointestinal toxicitiesencountered in the saquinavir-SGC study arm of MaxC-min 2 were attributed to the glyceride capmul componentSaquinavir is available in 2 formulations: the SGC formu-lation, Fortovase, and the original hard capsule (HC)saquinavir mesylate formulation, Invirase. In the presentstudy, the SGC formulation of saquinavir was used. As asole PI (unboosted), the oral bioavailability and effective-ness of saquinavir with the SGC formulation is higherthan that of the HC formulation. This difference is due tothe glyceride excipient component of the SGC formula-tion, capmul, which allows saquinavir to dissolve and dis-perse rapidly upon administration. However, the SGCformulation is associated with more gastrointestinaladverse events.[22,23] In a recent study of the saquinavir/ritonavir boosted regimen, the HC formulation ofsaquinavir mesylate demonstrated similar exposure to theSGC formulation but was better tolerated.[22,24] Conse-quently, it might be expected that the tolerability issuesencountered in this study could be ameliorated if the HCsaquinavir mesylate formulation of saquinavir was used.Interestingly, in a further study the boosted saquinavir-HC/ritonavir 1600 mg/100 mg regimen demonstratedpotent viral suppression (89% of patients had HIV RNAvalues < 50 copies/mL) with no patients withdrawingfrom the study due to adverse events.[25] Of note, thesaquinavir mesylate is now available as a 500-mg film-coated tablet, which is similar in size to the saquinavirmesylate 200 mg HC.Changes in lipid levels have been associated with the useof NRTIs and PIs and, consequently, the impact on lipidlevels should be an important consideration when choos-ing a treatment regimen.[26] With PIs, this risk has beenshown to be greatest with ritonavir, intermediate withamprenavir and nelfinavir, and lowest with indinavir andsaquinavir.[27,28] The recently approved PI, atazanavirappears to have little effect on lipid concentra-tions.[16,27] The lower doses of ritonavir (100200 mg)that are suitable for boosted saquinavir/ritonavir regi-mens may result in some increases of fasting triglycerideand cholesterol levels.[29] The data from this study con-firm a low lipid profile risk associated with a once-dailysaquinavir-SGC/ritonavir dose of 1600 mg/100 mg. Dur-ing this study, data evolved regarding the contribution ofNRTIs to hyperlipidemia and a post-hoc analysis was con-ducted that demonstrated that the predicting factor forhyperlipidemia in this study appeared to be the use of sta-vudine as the background NRTI.[30]Efavirenz once daily is a highly effective and commonlyprescribed part of ARV therapy; however, it may not besuitable for all patients. Patients taking efavirenz mayexperience central nervous system adverse events such asdizziness, insomnia, poor concentration, and vividdreams.[8] With the recent classification of efavirenz asPage 9 of 12(page number not for citation purposes)of the SGC formulation of saquinavir. pregnancy category D caution, it is advised in the treat-ment of women of child-bearing potential. Also, efavirenzJournal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36use may be a cause for concern in drug users currently tak-ing methadone because efavirenz-mediated reduction ofmethadone blood concentrations has also beenreported.[31,32] No methadone dose adjustments havebeen found to be required in patients receiving once-dailysaquinavir/ritonavir 1600 mg/100 mg therapy.[33]The results of the pharmacokinetic sub-analysis illustratedthat a once-daily regimen including saquinavir-SGC/ritonavir 1600 mg/100 mg provides a median AUC024 h of66,920 ng.h/mL. This is significantly higher than might beanticipated following the unboosted saquinavir SGC regi-men of 1200 mg 3 times daily, where the AUC08 h is 7249ng.h/mL.[34] In addition, the median observed Cmin at 24hours for saquinavir-SGC of 429 ng/mL was substantiallyhigher than the EC50 value of 50 ng/mL.[20] There is someevidence that failure on PI therapy can be linked to lowplasma concentrations,[35] but in this study no relation-ship was found between HIV RNA concentrations andsaquinavir Cmin values.[36] Currently, with antiretroviraltherapy, it is unknown which pharmacokinetic parametercorrelates best with efficacy.[37] While there is some evi-dence that failure on PI therapy can be linked to low Cminplasma concentrations,[20] in this study no relationshipwas found between HIV RNA concentrations and saquina-vir Cmin values.In conclusion, once-daily efavirenz was statistically supe-rior to the saquinavir-SGC/ritonavir (1600 mg/100 mg)once-daily regimen, as part of combination ARV therapy.Gastrointestinal adverse effects were commonly associ-ated with (ITT) treatment failure in the saquinavir-SGC/ritonavir arm of the study, which may be attributed to theSGC formulation used in this study. Future studies shouldevaluate the use of the saquinavir mesylate formulation,which has demonstrated similar exposure to the ritonavir-boosted SGC formulation with a better tolerability profileand by virtue of the 500-mg tablet also provides a lowerpill burden.Authors and DisclosuresJulio S.G. Montaner, MD, has disclosed that he hasreceived grant support from Abbott Laboratories,Agouron (a Pfizer company), Avexa Ltd, Boehringer Ingel-heim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sci-ences, GlaxoSmithKline, Hoffman-La Roche, Incyte,Merck Frosst Laboratories, Pfizer Canada, Tibotec Phar-maceuticals, and Trimeris.Malte Schutz, MD, has disclosed that he is an employee ofRoche Laboratories.Robert Schwartz, MD, has disclosed that he has served onDushyantha T. Jayaweera, MD, has disclosed that he hasserved on the speaker's bureau and/or received grant sup-port from Hoffman-La Roche, Bristol-Myers Squibb, Glax-oSmithKline, Boehringer Ingelheim Pharmaceuticals, andTibotec Pharmaceuticals.Alfred F. Burnside, MD, has disclosed no relevant finan-cial relationships.Sharon Walmsley, MD, has disclosed that she has servedon the speaker's bureau and advisory boards for Hoffman-La Roche, Bristol-Myers Squibb, GlaxoSmithKline, AbbottLaboratories, Merck, Gilead Sciences and Pfizer.Michael S. Saag, MD, has disclosed that he has served as aconsultant to and been a member of the speaker's bureauof Achillion Pharmaceutical, Boehringer Ingelheim, Bris-tol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pan-acos, Agouron (a Pfizer company), Progenics, RocheLaboratories, Tanox, Tibotec-Virco, Trimeris, Vertex, andViroLogic. He has also disclosed that he has receivedgrant/research support from Gilead Sciences, GlaxoSmith-Kline, Panacos, Agouron (a Pfizer company), Roche Lab-oratories, Serono, and Tibotec, Inc.FOCUS Study TeamNicholaos Bellos, MD, Southwest Infectious Disease Asso-ciates, Dallas, Texas; Alfred F. Burnside Jr, MD, BurnsideClinic, Columbia, South Carolina; Joseph Cervia, MD,Comprehensive HIV Center, New Hyde Park, New York;Ann C. Collier, MD, University of Washington School ofMedicine, Seattle, Washington; Paul Cook, MD, ECUSchool of Medicine, Greenville, North Carolina; StephenFollansbee, MD, HIV Clinical Trials Unit, San Francisco,California; Joseph C. Gathe Jr, MD, Houston, Texas; BruceHathaway, MD, ECU School of Medicine, Greenville,North Carolina; Margaret Hoffman-Terry, MD, LehighValley Hospital AAO, Allentown, Pennsylvania; Dushyan-tha T. Jayaweera, MD, University of Miami School of Med-icine, Miami, Florida; Jazila Alattar Mantis, MD, QueensHospital Center, Jamaica, New York; Joseph Masci, MD,Elmhurst Medical Center, Elmhurst, New York; Julio S.G.Montaner, MD, St Paul's Hospital, Vancouver, BritishColumbia, Canada; Mahmoud Mustafa, MD, Physicians'Home Service PC, Washington, DC; Kristin Ries, MD,University of Utah, Salt Lake City, Utah; Robert J. Roland,DO, Infectious Disease Specialists, Union, New Jersey;Danielle Rouleau, MD, CHUM, Montreal, Quebec;Michael S. Saag, MD, AIDS Outpatient Clinic, Birming-ham, Alabama; Stefan Schneider, MD, Living Hope Clini-cal Trials, Long Beach, California; John Schrank, MD, IDCare Center, Greenville, South Carolina; Malte Schutz,MD, Illinois Masonic Medical Center, Chicago, Illinois;Page 10 of 12(page number not for citation purposes)the Advisory Board for Roche and GlaxoSmithKline. Robert Schwartz, MD, Associates in Research, Fort Myers,Florida; Gladys Sepulveda, MD, Anexo Hospital Oncolog-Journal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/36ica, Ponce, Puerto Rico; Leon Smith, MD, St Michael'sMedical Center, Newark, New Jersey; Joseph Timpone,MD, Georgetown University Hospital, Washington, DC;Paul Volberding, MD, UCSF AIDS Program, San Fran-cisco, California; Sharon Walmsley, MD, The TorontoHospital, Toronto, Ontario.Funding InformationThis study was supported by a research grant from RochePharmaceuticals.AcknowledgementsWe thank Pascal J. de Caprariis, MD, and Huilin Hu for assistance with the trial. We also would like to express our thanks to the study coordinators from all investigational sites.References1. Palella FJ, Delaney KM, Moorman AC, et al.: Declining morbidityand mortality among patients with advanced human immu-nodeficiency virus infection. HIV Outpatient Study Investiga-tors.  N Engl J Med 1998, 338:853-860. Abstract2. Detels R, Munoz A, McFarlane G, et al.: Effectiveness of potentantiretroviral therapy on time to AIDS and death in menwith known HIV infection duration. AIDS Cohort StudyInvestigators.  JAMA 1998, 280:1497-503. Abstract3. Bartlett JA, DeMasi R, Quinn J, et al.: Overview of the effective-ness of triple combination therapy in antiretroviral-naiveHIV-1 infected adults.  AIDS 2001, 15:1369-1377. Abstract4. Altice FL, Friedland GH: The era of adherence to HIV therapy.Ann Intern Med 1998, 129:503-505.5. Monforte d'Arminio A, Lepri AC, Rezza G, et al.: Insights into thereasons for discontinuation of the first highly active antiret-roviral therapy (HAART) regimen in a cohort of antiretrovi-ral naive patients. I.CO.N.A. Study Group. Italian Cohort ofAntiretroviral-Naive Patients.  AIDS 2000, 14:499-507. Abstract6. Cohen CJ, Hellinger J, Norris D: Evaluation of simplified pro-tease inhibitor dosing regimens for the treatment of HIVinfection.  AIDS Read 2000, 10:296-299. 304307, 3113137. Staszewski S, Morales-Ramirez J, Tashima KT, et al.: Efavirenz pluszidovudine and lamivudine, efavirenz plus indinavir, and indi-navir plus zidovudine and lamivudine in the treatment ofHIV-1 infection in adults.  N Engl J Med 1999, 341:1865-1873.Abstract8. Sustiva (efavirenz capsules and tablets).  In US Prescribing Infor-mation New Jersey: Bristol-Myers Squibb; 2002. 9. DHHS Guidelines: Guidelines for the use of antiretroviralagents in HIV-infected adults and adolescents. US DeptHealth and Human Services Panel on Clinical Practices forTreatment of HIV Infection.  Guidelines for the Use of AntiretroviralAgents in HIV-1-Infected Adults and Adolescents 2005 [http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf].10. BHIVA Writing Committee: British HIV association (BHIVA)guidelines for the treatment of HIV-infected adults withantiretroviral therapy.  HIV Med 2001, 2:276-313. Abstract11. Kilby JM, Hill A, Buss N: The effect of ritonavir on saquinavirplasma concentration is independent of ritonavir dosage:combined analysis of pharmacokinetic data from 97 subjects.HIV Med 2002, 3:97-104. Abstract12. Cardiello PG, Van Heeswijk RP, Hassink EA, et al.: Simplifying pro-tease inhibitor therapy with once-daily dosing of saquinavirsoft-gelatin capsules/ritonavir (1600 mg/100 mg): HIVNAT001.3 study.  J Acquir Immune Defic Syndr 2002, 29:464-470. Abstract13. Arasteh K, Wood R, Teofilo E, et al.: Amprenavir (APV) 600 mg/ritonavir (RTV) 100 mg BID or APV 1200 mg/RTV 200 mgQD given in combination with abacavir (ABC) and lamivu-dine (3TC) maintains efficacy in ART naive HIV-1 infectedadults over 24 weeks (APV20001).  Eighth European Conference onClinical Aspects and Treatment of HIV Infection, Athens, Greece, Octobersus twice-daily nelfinavir in naive HIV-1-infected patients.AIDS 2004, 8:1529-1537.15. Eron J, Bernstein B, King M, et al.: Once-daily versus twice dailyKaletra (lopinavir/ritonavir) in antiretroviral-naive HIV+patients: 48 week follow-up.  Ninth Conference on Retroviruses andOpportunistic Infections, Seattle, Washington, February 2428, 2002 .Abstract 40916. Piliero PJ: Atazanavir: A novel once-daily protease inhibitor.Drugs Today (Barc) 2004, 40(11):901-912.17. Peytavin G, Landman R, Lamotte C, et al.: Saquinavir (SQV)plasma and intracellular concentrations in a once daily dos-ing combination Fortovase[R] (SQV-SGC)-low dose ritona-vir (RTV) in a prospective study (IMEA 015) in HIV-infectedpatients.  Second International Workshop on Clinical Pharmacology ofHIV Therapy, Noordwijk, The Netherlands 2001. Abstract 3.1618. Buss N, Snell P, Bock J, et al.: Saquinavir and ritonavir pharma-cokinetics following combined ritonavir and saquinavir (softgelatin capsules) administration.  J Clin Pharmacol 2001,52:255-264.19. Farrington CP, Manning G: Test statistics and sample size for-mulae for comparative binomial trials with null hypothesis ofnon-zero risk difference or non-unity relative risk.  Stat Med1990, 9:1447-1454. Abstract20. Gieschke R, Fotteler B, Buss N, et al.: Relationships betweenexposure to saquinavir monotherapy and antiviral responsein HIV-positive patients.  Clin Pharmacokinet 1999, 37:75-86.Abstract21. Youle M, Gerstoft J, Fox Z, et al.: The final 48 week analysis of aphase IV, randomized, open-label, multicentre trial to eval-uate safety and efficacy of lopinavir/ritonavir (400/100 mgBID) versus saquinavir/ritonavir (1000/100 mg BID): theMaxCmin 2 trial.  Program and abstracts of the 9th European AIDSConference (EACS), Warsaw 2003. Abstract F11/322. Kurowski M, Sternfeld T, Sawyer A, et al.: Pharmacokinetic andtolerability profile of twice-daily saquinavir hard gelatin cap-sules and saquinavir soft gelatin capsules boosted with riton-avir in healthy volunteers.  HIV Med 2003, 4:94-100. Abstract23. Mitsuyasu RT, Skolnik PR, Cohen SR, et al.: Activity of the soft gel-atin formulation of saquinavir in combination therapy inantiretroviral-naive patients.  AIDS 1998, 12:F103-109. Abstract24. Cardiello P, Monhaphol T, Mahanontharit A, et al.: Pharmacokinet-ics (PK) of once daily saquinavir-hard gels caps (SQV-HGC)and saquinavir-soft gel caps (SQV-SGC) boosted with riton-avir (RTV) in HIV-1+ Thai patients: HIV NAT001.4 substudy.Program and abstracts of the 3rd International Workshop on Clinical Phar-macology of HIV Therapy, Washington DC 2002. Abstract 1.225. Ananworanich J, Hill A, Siangphoe U, Ruxrungtham K, et al.: StaccatoStudy Group. A prospective study of efficacy and safety ofonce-daily saquinavir/ritonavir plus two nucleoside reversetranscriptase inhibitors in treatment-naive Thai patients.Antivir Ther 2005, 10:761-767. Abstract26. Dale E, Manuney J, Uffelman K, et al.: Incidence of lipodystrophyin START (Selection of Thymidine Analog Regimen Ther-apy) Studies.  Program and abstracts of the 1st International Workshopon Adverse Drug Reactions and Lipodystrophy in HIV; June 2628, SanDiego, California 1999. Abstract 3027. Dube MP, Stein JH, Aberg JA, et al.: Adult AIDS Clinical TrialsGroup Cardiovascular Subcommittee; HIV Medical Associa-tion of the Infectious Disease Society of America. Guidelinesfor the evaluation and management of dyslipidemia inhuman immunodeficiency virus (HIV)-infected adults receiv-ing antiretroviral therapy: recommendations of the HIVMedical Association of the Infectious Disease Society ofAmerica and the Adult AIDS Clinical Trials Group.  Clin InfectDis 2003, 37:613-627. Abstract28. Moyle GJ, Baldwin C: Lipid abnormalities during saquinavir softgel-based highly active antiretroviral therapy.  Program andabstracts of the 39th Interscience Conference on Antimicrobial Agents andChemotherapy; September 2629, 1999; San Francisco, California .Abstract 129229. O'Brien WA, Rojo D, Acosta E, et al.: Switch of Saquinavir 400mg/ritonavir 400 mg to saquinavir 1000 mg/ritonavir 100 mgduring BID four drug antiretroviral therapy in patients withviral load less than 200 copies/mL.  Program and abstracts of thePage 11 of 12(page number not for citation purposes)2831, 2001 . Abstract 21814. Gathe JC Jr, Ive P, Wood R, et al.: SOLO: 48-week efficacy andsafety comparison of once-daily fosamprenavir/ritonavir ver-3rd International Workshop on Clinical Pharmacology of HIV Therapy; April1113, 2002; Washington, DC . Abstract 2.1Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central Journal of the International AIDS Society 2006, 8:36 http://www.jiasociety.org/content/8/2/3630. Walmsley S, Montaner J, Hill A, et al.: Nucleoside reverse tran-scriptase inhibitor treatment as a risk factor for hyperlipi-demia: results from the FOCUS trial.  Antiviral Ther 2002, 7:L35.31. Marzolini C, Troillet N, Telenti A, et al.: Efavirenz decreasesmethadone blood concentrations.  AIDS 2000, 14:1291-1292.Abstract32. Clarke SM, Mulcahy FM, Tija J, et al.: The pharmacokinetics ofmethadone in HIV-positive patients receiving the non-nucle-oside reverse transcriptase inhibitor efavirenz.  Br J Clin Phar-macol 2001, 51:213-217. Abstract33. Munsiff AV, Einstein Coll A, Patel J: Regimens with once dailyritonavir + Fortovase are highly effective in PI-experiencedHIV-HCV co-infected patients on Methadone.  Program andabstracts of the 39th Annual Meeting of the Infectious Diseases Society ofAmerica (IDSA); October 2528, 2001; San Francisco, California . Abstract68434. Fortovase: EU Summary of Product Characteristics.  2006[http://www.emea.eu.int/humandocs/PDFs/EPAR/Fortovase/H-178-PI-en.pdf]. Accessed April 2135. Durant J, Clevenbergh P, Garraffo R, et al.: Importance of proteaseinhibitor plasma levels in HIV-infected patients treated withgenotypic-guided therapy: pharmacological data from theViradapt study.  AIDS 2000, 14:1333-1339. Abstract36. Schutz M, Goodly J, Chen K, et al.: Lack of correlation betweensaquinavir trough levels and adverse events or clinical out-comes in saquinavir cohort of focus study.  Program and abstractsof the 41st Annual Meeting of the Infectious Diseases Society of America(IDSA); October 912, 2003; San Diego . Poster 105937. Back DJ, Khoo SH, Gibbons SE, et al.: The role of therapeutic drugmonitoring in treatment of HIV infection.  Br J Clin Pharmacol2001, 51:301-308. Abstractyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 12 of 12(page number not for citation purposes)


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