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Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.

ABSTRACT: OBJECTIVES:Cobicistat (COBI) enhances atazanavir (ATV) pharmacokinetic parameters similarly to ritonavir (RTV) in both healthy volunteers and HIV-infected adults. Primary efficacy and safety outcomes of this Phase 3, international, randomized, double-blind, double-dummy, active- controlled trial in HIV-1-infected treatment-naïve adults (GS-US-216-0114/NCT01108510) demonstrated that ATV+COBI was non-inferior to ATV+RTV, each in combination with emtricitabine/ tenofovir disoproxil fumarate (FTC/TDF), at Weeks 48 and 144, with high rates of virologic success for both regimens (85.2% and 87.4%, respectively, at Week 48; and 72.1% and 74.1% at Week 144), and with comparable safety and tolerability. Here, we describe virologic response and treatment discontinuation by a wider range of subgroups than previously presented. METHODS:Subgroup analyses by baseline CD4 count (?200, 201-350, >350 cells/mm3), baseline HIV-1 RNA level (?100,000, >100,000 copies/mL), race, sex, and age (<40, ?40 years) evaluated ATV+COBI versus ATV+RTV univariate odds ratios (ORs) for virologic success (viral load <50 copies/mL, intention-to-treat US Food and Drug Administration Snapshot algorithm) and discontinuation due to adverse events (AEs) at Weeks 48 and 144. Of 692 patients randomized, 344 received ATV+COBI and 348 ATV+RTV. RESULTS:ATV+COBI versus ATV+RTV ORs for virologic success did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.90; 95% confidence interval [CI]: 0.64, 1.26) or within subgroups, except in females, for whom ATV+COBI was favored at Week 144 (OR 2.36; 95% CI: 1.02, 5.47). However, there were more discontinuations due to withdrawal of consent and pregnancies in females receiving ATV+RTV versus ATV+COBI. ORs for discontinuation due to AEs did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.98; 95% CI: 0.61, 1.58) or within subgroups. CONCLUSION:These findings indicate that both ATV+COBI and ATV+RTV, each with FTC/TDF, are effective and well-tolerated treatment options across a wide demographic range of HIV-infected patients.

SUBMITTER: Gallant J

PROVIDER: S-EPMC5543662 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.

Gallant Joel J Moyle Graeme G Berenguer Juan J Shalit Peter P Cao Huyen H Liu Ya-Pei YP Myers Joel J Rosenblatt Lisa L Yang Lingfeng L Szwarcberg Javier J

Current HIV research 20170101 3

<h4>Objectives</h4>Cobicistat (COBI) enhances atazanavir (ATV) pharmacokinetic parameters similarly to ritonavir (RTV) in both healthy volunteers and HIV-infected adults. Primary efficacy and safety outcomes of this Phase 3, international, randomized, double-blind, double-dummy, active- controlled trial in HIV-1-infected treatment-naïve adults (GS-US-216-0114/NCT01108510) demonstrated that ATV+COBI was non-inferior to ATV+RTV, each in combination with emtricitabine/ tenofovir disoproxil fumarate ...[more]

PMID: 27774892

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Project description:Background Women and those with non-B subtype HIV-1 are typically underrepresented in clinical trials. WAVES (GS-US-236-0128) was a double-blind phase 3b study among treatment-naïve HIV-1-infected women that demonstrated that elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF; N = 289) was superior to atazanavir + ritonavir + FTC/TDF (ATV + RTV + FTC/TDF; N = 286) for HIV-1 RNA < 50 copies/mL by FDA snapshot analysis at week 48. Here, we describe resistance development through week 48 in women with virologic failure and determine the impact of pre-existing mutations and HIV-1 subtype on viral suppression. Methods Genotypic analyses (population and deep sequencing) and phenotypic analyses of HIV-1 protease, reverse transcriptase (RT), and integrase (IN) were performed. The resistance analysis population (participants with HIV-1 RNA ≥ 400 copies/mL at confirmed virologic failure, at discontinuation ≥ week 8, or at week 48) had genotypic and phenotypic analyses at failure and baseline. Results The proportion of women qualifying for resistance analyses was similar between treatment groups (6.2% EVG/COBI/FTC/TDF; 7.3% ATV + RTV + FTC/TDF). Emergent resistance was rare (0% EVG/COBI/FTC/TDF; 1% ATV + RTV + FTC/TDF - 3 with M184V/I in RT). Deep sequencing of HIV-1 did not detect additional resistance development. Pre-existing mutations did not lead to virologic failure; most with the polymorphic primary IN substitution T97A (92%), or with substitutions in RT (i.e. A62V, V90I, K103N, or E138A/G/K/Q; 68-82%) demonstrated virologic suppression at week 48, with no resistance development except for one patient with M184V and pre-existing K103N in the ATV + RTV + FTC/TDF group. Most participants (74%) had non-B HIV-1, and subtype did not affect outcome. Conclusions Emergent resistance to study drugs was rare in this study of women, with no resistance observed among EVG/COBI/FTC/TDF-treated participants, despite a high proportion of participants with natural or transmitted viral mutations and non-B HIV-1 subtypes.

Project description:BackgroundThe recent discovery that a combination of noradrenergic and antimuscarinic drugs improved upper airway muscle function during sleep and reduced OSA severity has revitalized interest in pharmacologic therapies for OSA.Research questionWould 1 week of reboxetine plus oxybutynin (Reb-Oxy) be effective on OSA severity?Study design and methodsA randomized, placebo-controlled, double-blind, crossover trial was performed comparing 4 mg reboxetine plus 5 mg oxybutynin (Reb-Oxy) vs placebo in patients with OSA. After a baseline in-laboratory polysomnogram (PSG), patients underwent PSGs after 7 nights of Reb-Oxy and 7 nights of placebo to compare apnea-hypopnea index (AHI), which was the primary outcome. Response rate was based on the percentage of subjects with a ≥ 50% reduction in AHI from baseline. Secondary outcomes included Epworth Sleepiness Scale (ESS) score and psychomotor vigilance test (PVT) values. Home oximetry evaluated overnight oxygen desaturation index (ODI) throughout treatment.ResultsSixteen subjects aged 57 [51-61] years (median [interquartile range]) with a BMI of 30 [26-36] kg/m2 completed the study. Reb-Oxy lowered AHI from 49 [35-57] events per hour at baseline to 18 [13-21] events per hour (59% median reduction) compared with 39 [29-48] events per hour (6% median reduction) with placebo (P < .001). Response rate for Reb-Oxy was 81% vs 13% for placebo (P < .001). Although ESS scores were not significantly lowered, PVT median reaction time decreased from 250 [239-312] ms at baseline to 223 [172-244] ms on Reb-Oxy vs 264 [217-284] ms on placebo (P < .001). Home oximetry illustrated acute and sustained improvement in the oxygen desaturation index on Reb-Oxy vs placebo.InterpretationThe administration of Reb-Oxy greatly decreased OSA severity and increased vigilance. These results highlight potential possibilities for pharmacologic treatment of OSA.Clinical trial registrationClinicalTrials.gov; No.: NCT04449133; URL: www.clinicaltrials.gov.

Project description:OBJECTIVES:To investigate efficacy and safety of a single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infected adults. DESIGN:Phase-3, randomized, active-controlled, double-blind, international, multicenter, noninferiority study (NCT02431247). METHODS:Seven hundred and twenty-five participants were randomized (1 : 1) to D/C/F/TAF (362) or control (363). The primary objective was to demonstrate noninferiority of D/C/F/TAF vs. control for percentage viral load less than 50 copies/ml (FDA-snapshot analysis) at 48 weeks (10% margin). RESULTS:At week 48, D/C/F/TAF was noninferior to control (91.4 vs. 88.4% achieved viral load <50 copies/ml, respectively; difference 2.7%; 95% CI -1.6 to 7.1; P < 0.0001), with 4.4 vs. 3.3% of patients, respectively, having viral load greater or equal to 50 copies/ml. No treatment-emergent mutations associated with darunavir or TAF/TDF resistance were observed in either group. One patient (D/C/F/TAF) was identified with M184I/V conferring resistance to emtricitabine. Incidences of grades 3 and 4 adverse events (5 vs. 6%), serious adverse events (5 vs. 6%) and adverse event-related discontinuations (2 vs. 4%) were low and similar between groups. Mean decrease in urine protein/creatinine ratio was greater with D/C/F/TAF than control (-22.42 vs. -10.34 mg/g, P = 0.033). Mean percentage change in bone mineral density with D/C/F/TAF vs. control was 0.21 vs. -2.73%, P < 0.0001 (hip), -0.68 vs. -2.38%, P = 0.004 (lumbar spine), and -0.26 vs. -2.97%, P < 0.0001 (femoral neck). Median change from baseline in total cholesterol/HDL-cholesterol ratio was 0.20 vs. 0.08, P = 0.036. CONCLUSION:D/C/F/TAF achieved a high virologic suppression rate (91.4%) and was noninferior to darunavir/cobicistat with F/TDF. D/C/F/TAF also demonstrated the bone and renal safety advantages of TAF in combination with darunavir/cobicistat.

Project description:BackgroundCobicistat is an alternative pharmacoenhancer to ritonavir. In healthy volunteers, darunavir exposure was comparable when darunavir 800 mg once daily was co-administered with cobicistat 150 mg once daily (as single agents or a fixed-dose combination) vs. with ritonavir 100 mg once daily.MethodsThis 48-week, Phase IIIb, single-arm, US multicenter study (NCT01440569) evaluated safety, efficacy and pharmacokinetics of darunavir/cobicistat 800/150 mg once daily (as single agents) plus two investigator-selected nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) in HIV-1-infected adults. Patients had no darunavir resistance-associated mutations (RAMs), plasma viral load (VL) ≥1000 HIV-1 RNA copies/ml, eGFR ≥80 ml/min and genotypic sensitivity to the two N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 adverse events (AEs) through Week 24.ResultsThe majority of the 313 intent-to-treat patients were treatment-naïve (295/313; 94%), male (89%), White (60%) and received a tenofovir-based regimen (99%). Median baseline VL and CD4(+) count overall were 4.8 log10 HIV-1 RNA copies/ml and 361 cells/mm(3), respectively. Overall, 86% of patients (268/313) completed the study. The majority of discontinuations were for AEs (15/313; 5%). The incidence of treatment-emergent grade 3 or 4 AEs regardless of causality was 6% through Week 24 and 8% through Week 48. Most common AEs through Week 48 were diarrhea (27%) and nausea (23%), which were grade 1 or 2 in severity. Week 48 virologic response rates (% with VL <50 HIV-1 RNA copies/ml; Snapshot analysis) were 81% overall and 83% in treatment-naïve patients; median increases in CD4(+) count at 48 weeks were 167 and 169 cells/mm(3), respectively. Of 15/313 patients who met the criteria for resistance analysis, one developed a darunavir RAM as a mixture with wild-type (I84I/V), without phenotypic resistance to darunavir. The mean population pharmacokinetic-derived darunavir areas under the plasma concentration-time curve were 102,000 overall and 100,620 ng•h/ml in treatment-naïve patients. No clinically relevant relationships were seen between darunavir exposure and virologic response, AEs or laboratory parameters.ConclusionDarunavir/cobicistat 800/150 mg once daily was generally well tolerated through Week 48, with no new safety concerns. Pharmacokinetics, virologic and immunologic responses for darunavir/cobicistat were similar to previous data for darunavir/ritonavir 800/100 mg once daily.

Project description:BackgroundTafolecimab, a fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody developed for the treatment of hypercholesterolemia, demonstrated robust lipid-lowering efficacy and favorable safety in previous short-term studies. We aimed to assess the long-term efficacy and safety of tafolecimab in Chinese non-familial hypercholesterolemia (non-FH) patients.MethodsNon-FH patients at high or very-high cardiovascular risk with screening low-density lipoprotein cholesterol (LDL-C) level ≥1.8 mmol/L or non-FH patients with screening LDL-C level ≥3.4 mmol/L and on stable lipid-lowering therapy for at least 4 weeks, were randomized in a 2:2:1:1 ratio to receive subcutaneous tafolecimab 450 mg Q4W, tafolecimab 600 mg Q6W, placebo 450 mg Q4W, or placebo 600 mg Q6W, respectively, in the 48-week double-blind treatment period. The primary endpoint was the percent change from baseline to week 48 in LDL-C levels.FindingsA total of 618 patients were randomized and 614 patients received at least one dose of tafolecimab (n = 411) or placebo (n = 203). At week 48, tafolecimab induced significant reductions in LDL-C levels (treatment differences versus placebo [on-treatment estimand]: -65.0% [97.5% CI: -70.2%, -59.9%] for 450 mg Q4W; -57.3% [97.5% CI: -64.0%, -50.7%] for 600 mg Q6W; both P < 0.0001). Significantly more patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C < 1.8 mmol/L, and LDL-C < 1.4 mmol/L than placebo group at both dose regimens (all P < 0.0001). Furthermore, tafolecimab significantly reduced non-HDL-C, apolipoprotein B, and lipoprotein(a) levels. The most commonly-reported treatment emergent adverse events in the tafolecimab groups included upper respiratory infection, urinary tract infection and hyperuricemia.InterpretationTafolecimab dosed at 450 mg Q4W and 600 mg Q6W was safe and showed superior lipid-lowering efficacy versus placebo, providing a novel treatment option for Chinese hypercholesterolemia patients.FundingThis study was sponsored by Innovent Biologics, Inc.

Project description:PurposeThe 144-week results of the open-label, multicenter Atazanavir/Ritonavir Induction with Epzicom Study (ARIES) were stratified by gender to compare treatment responses.MethodsA total of 369 HIV-infected, antiretroviral-naïve subjects receiving once-daily abacavir/lamivudine + atazanavir/ritonavir (ATV/r) whose HIV-1 RNA was <50 copies/mL by week 30 were randomized 1:1 at week 36 to maintain or discontinue ritonavir for 108 subsequent weeks. Between- and within-treatment gender-related efficacy and safety differences were analyzed.ResultsSubjects were 85% male; 64% white; and had a mean age of 39 years, baseline median HIV-1 RNA of 114,815 copies/mL, and median CD4+ cell count of 198 cells/mm3. Gender (ATV [n=189]: 29 females/160 males; ATV/r [n=180]: 25 females/155 males) and most other demographics were similar between groups; more females than males were black (65% vs 25%) and fewer females had baseline HIV-1 RNA ≥100,000 copies/mL (41% vs 58%). At week 144, no significant differences between genders were observed in proportion maintaining HIV-1 RNA <50 copies/mL (ATV, 79% vs 77%; ATV/r, 60% vs 75%) or <400 copies/mL (ATV, 83% vs 84%; ATV/r, 68% vs 82%) (intent-to-treat-exposed: time to loss of virologic response analysis); median CD4+ change from baseline (ATV, +365 vs +300 cells/mm3; ATV/r, +344 vs +301 cells/mm3); proportion with treatment-related grade 2-4 adverse events (baseline to week 144: ATV, 41% vs 31%; ATV/r, 36% vs 43%; weeks 36 to 144: ATV, 14% vs 13%; ATV/r, 24% vs 23%); or proportion developing fasting lipid changes. Female and male virologic failure rates (ATV, 0 vs 5; ATV/r, 2 vs 4) and proportions completing the study were similar during the extension phase. Primary withdrawal reasons were loss to follow-up and pregnancy for females and loss to follow-up and other for males.ConclusionOver 144 weeks, no significant gender differences were observed in efficacy, safety, or fasting lipid changes with abacavir/lamivudine +ATV or abacavir/lamivudine +ATV/r.

Project description:BackgroundTenofovir disoproxil fumarate (TDF) has been widely recommended as a first-line antiviral agent to treat chronic hepatitis B (CHB). Qingzhong and Viread, formulations of TDF commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd and GlaxoSmithKline, respectively, have both been approved by the State Food and Drug Administration, China. This study analyzed the efficacy and safety of these 2 TDF agents in Chinese patients with CHB.MethodsIn this multicenter, randomized, double-blind, double-dummy, noninferiority phase 3 clinical trial (ClinicalTrials.gov identifier: NCT02287857), 330 Chinese patients with CHB [hepatitis B envelope antigen-positive (HBeAg) (+): 232] were randomly assigned to receive Qingzhong (group A: 161 patients) or Viread (group B: 169 patients) 300 mg once daily for 48 weeks. Subsequently, all patients were administered Qingzhong 300 mg once daily from week 49 to week 240. The primary end point was the degree of decline of plasma hepatitis B virus (HBV) DNA levels at week 48 and the secondary endpoints were viral suppression, normalization of alanine aminotransferase (ALT) levels, hepatitis B surface antigen (HBsAg)/HBeAg loss or seroconversion, and virological breakthrough.ResultsAmong patients with CHB who were HBeAg (+), the mean HBV DNA titer decreased similarly between the groups at week 48. The percentages of patients who achieved undetectable HBV DNA were similar between the groups (85.11% and 82.35% in groups A and B, respectively) and similar losses of HBeAg and HBeAg seroconversion rates were achieved. Moreover, for patients with CHB who were HBeAg (-), reductions in HBV DNA were similar. Among all patients with CHB, the rates of normalization of ALT and the loss of HBsAg were similar. The overall incidence of adverse events was comparable between the groups.ConclusionIn conclusion, the 48-week administration of Qingzhong showed noninferior efficacy and safety profiles compared to Viread in Chinese patients with CHB.

Project description:We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150 mg plus lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (ANV/3TC/TDF), or cobicistat (Cobi) 150 mg boosted EVG plus emtricitabine (FTC) 200 mg, and tenofovir alafenamide (TAF) 10 mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n = 381) or EVG/Cobi/FTC/TAF (n = 381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI -1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05 kg, ETD -0.90 kg, 95% CI, -1.43 to -0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.

Dataset Information

Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.

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Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.

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