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Although concern is frequently expressed regarding the potential impact of baby food pouch use and Baby-Led Weaning (BLW) on infant health, research is scarce. Data on pouch use, BLW, energy intake, eating behaviour and body mass index (BMI) were obtained for 625 infants aged 7-10 months in the First Foods New Zealand study. Frequent pouch use was defined as ≥5 times/week during the past month. Traditional spoon-feeding (TSF), "partial" BLW and "full" BLW referred to the relative proportions of spoon-feeding versus infant self-feeding, assessed at 6 months (retrospectively) and current age. Daily energy intake was determined using two 24-h dietary recalls, and caregivers reported on a variety of eating behaviours. Researchers measured infant length and weight, and BMI z-scores were calculated (World Health Organization Child Growth Standards). In total, 28% of infants consumed food from pouches frequently. Frequent pouch use was not significantly related to BMI z-score (mean difference, 0.09; 95% CI -0.09, 0.27) or energy intake (92 kJ/day; -19, 202), but was associated with greater food responsiveness (standardised mean difference, 0.3; 95% CI 0.1, 0.4), food fussiness (0.3; 0.1, 0.4) and selective/restrictive eating (0.3; 0.2, 0.5). Compared to TSF, full BLW was associated with greater daily energy intake (BLW at 6 months: mean difference 150 kJ/day; 95% CI 4, 297; BLW at current age: 180 kJ/day; 62, 299) and with a range of eating behaviours, including greater satiety responsiveness, but not BMI z-score (6 months: 0.06 (-0.18, 0.30); current age: 0.06 (-0.13, 0.26)). In conclusion, neither feeding approach was associated with weight in infants, despite BLW being associated with greater energy intake compared with TSF. However, infants who consumed pouches frequently displayed higher food fussiness and more selective eating.
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Ingestão de Energia , Fenômenos Fisiológicos da Nutrição do Lactente , Humanos , Lactente , Comportamento Alimentar , Comportamento do Lactente , Alimentos Infantis , Estudos Retrospectivos , DesmameRESUMO
BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a once-daily, single-tablet regimen for treatment of HIV-1 infection. The efficacy/safety of switching to D/C/F/TAF versus continuing boosted protease inhibitor (bPI) + emtricitabine/tenofovir disoproxil fumarate (control) were demonstrated in a phase 3, randomized study (EMERALD) of treatment-experienced, virologically suppressed adults through week 48. The objective of this analysis was to evaluate EMERALD outcomes across subgroups of patients based on demographic characteristics, prior treatment experience, and baseline antiretroviral regimen. METHODS: EMERALD patients were virologically suppressed (viral load [VL] < 50 copies/mL for ≥ 2 months at screening). Prior non-darunavir virologic failure (VF) was allowed. Primary endpoint was proportion of patients with virologic rebound (confirmed VL ≥ 50 copies/mL) cumulative through week 48. Virologic response was VL < 50 copies/mL (FDA snapshot). Safety was assessed by adverse events, renal proteinuria markers, and bone mineral density. Outcomes were examined for prespecified subgroups by age (≤/> 50 years), gender, race (black/non-black), prior number of antiretrovirals used (4/5/6/7/> 7), prior VF (0/≥ 1), baseline bPI (darunavir/atazanavir or lopinavir), and baseline boosting agent (ritonavir/cobicistat). RESULTS: Among 1141 patients in the D/C/F/TAF (n = 763) and control (n = 378) arms, virologic rebound rates (2.5% and 2.1%, respectively) were similar, and this was consistent across all subgroups. Virologic response rates ranged from 91 to 97% (D/C/F/TAF) and 89 to 99% (control) across all subgroups, with differences between treatment arms of 0 and 6%. Adverse event rates were low in both arms and across subgroups. Improvements in renal and bone parameters were observed with D/C/F/TAF across demographic subgroups. CONCLUSIONS: For treatment-experienced, virologically suppressed patients, switching to D/C/F/TAF was highly effective and safe, regardless of demographic characteristics, prior treatment experience, or pre-switch bPI. Trial registration ClinicalTrials.gov Identifier: NCT02269917. Registered 21 October 2014. https://clinicaltrials.gov/ct2/show/NCT02269917.
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Fármacos Anti-HIV/uso terapêutico , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Carga Viral/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Idoso , Alanina , Terapia Antirretroviral de Alta Atividade , Cobicistat/uso terapêutico , Darunavir/uso terapêutico , Combinação de Medicamentos , Emtricitabina/uso terapêutico , Feminino , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/uso terapêutico , Resposta Viral Sustentada , Comprimidos , Tenofovir/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Obtaining valid estimates of nutrient intake in infants is currently limited by the difficulties of accurately measuring human milk intake. Current methods are either unsuitable for large-scale studies (i.e., the gold standard dose-to-mother stable isotope technique) or use set amounts, regardless of known variability in individual intake. OBJECTIVES: This cross-sectional study aimed to develop equations to predict human milk intake using simple measures and to carry out external validation of existing methods against the gold standard technique. METHODS: Data on human milk intake were obtained using the dose-to-mother stable isotope technique in 157 infants aged 7-10 mo and their mothers. Predictive equations were developed using questionnaire and anthropometric data (Model 1) and additional dietary data (Model 2) using lasso regression. Bland-Altman plots and intraclass correlation coefficients (ICC) also assessed the validity of existing methods (FITS and ALSPAC studies). RESULTS: The strongest univariate predictors of human milk intake in infants of 8.3 mo on average (46% female) were infant age, infant body mass index (BMI), number of breastfeeds a day, infant formula consumption, and energy from complementary food intake. Mean [95% confidence interval (CI)] differences in predicted versus measured human milk intake [mean (SD): 762 (257) mL/day] were 0.0 mL/day (-26, 26) for Model 1 (ICC 0.74) and 0.5 mL/day (-21, 22) for Model 2 (ICC 0.83). Corresponding differences were -197 mL/day (-233, -161; ICC 0.32) and -175 mL/day (-216, -134; ICC 0.41) for the methods used by FITS and ALSPAC, respectively. CONCLUSIONS: The Human Milk Intake Level Calculation provides substantial improvements on existing methods to estimate human milk intake in infants aged 7-10 mo, while utilizing data commonly collected in nutrition surveys. Although further validation in an external sample is recommended, these equations can be used to estimate human milk intake at this age with some confidence. This clinical trial was registered at http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379436) as ACTRN12620000459921.
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Fenômenos Fisiológicos da Nutrição do Lactente , Leite Humano , Humanos , Estudos Transversais , Lactente , Feminino , Masculino , Aleitamento Materno , Fórmulas Infantis , Dieta , Ingestão de Energia , Índice de Massa CorporalRESUMO
Iron deficiency in infants can impact development, and there are concerns that the use of baby food pouches and baby-led weaning may impair iron status. First Foods New Zealand (FFNZ) was an observational study of 625 New Zealand infants aged 6.9 to 10.1 months. Feeding methods were defined based on parental reports of infant feeding at "around 6 months of age": "frequent" baby food pouch use (five+ times per week) and "full baby-led weaning" (the infant primarily self-feeds). Iron status was assessed using a venepuncture blood sample. The estimated prevalence of suboptimal iron status was 23%, but neither feeding method significantly predicted body iron concentrations nor the odds of iron sufficiency after controlling for potential confounding factors including infant formula intake. Adjusted ORs for iron sufficiency were 1.50 (95% CI: 0.67-3.39) for frequent pouch users compared to non-pouch users and 0.91 (95% CI: 0.45-1.87) for baby-led weaning compared to traditional spoon-feeding. Contrary to concerns, there was no evidence that baby food pouch use or baby-led weaning, as currently practiced in New Zealand, were associated with poorer iron status in this age group. However, notable levels of suboptimal iron status, regardless of the feeding method, emphasise the ongoing need for paying attention to infant iron nutrition.
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Ferro , Estado Nutricional , Desmame , Humanos , Nova Zelândia/epidemiologia , Lactente , Feminino , Masculino , Ferro/sangue , Fenômenos Fisiológicos da Nutrição do Lactente , Alimentos Infantis/análise , Anemia Ferropriva/epidemiologia , Anemia Ferropriva/sangue , Deficiências de FerroRESUMO
Infant feeding guidelines provide evidence-based recommendations to support optimal infant health, growth, and development, and exploring adherence to guidelines is a useful way of assessing diet quality. The aim of this study was to determine adherence to the recently updated Ministry of Health "Healthy Eating Guidelines for New Zealand Babies and Toddlers (0-2 years old)". Data were obtained from First Foods New Zealand, a multicentre observational study of 625 infants aged 7.0-10.0 months. Caregivers completed two 24-h diet recalls and a demographic and feeding questionnaire. Nearly all caregivers (97.9%) initiated breastfeeding, 37.8% exclusively breastfed to around six months of age, and 66.2% were currently breastfeeding (mean age 8.4 months). Most caregivers met recommendations for solid food introduction, including appropriate age (75.4%), iron-rich foods (88.3%), puréed textures (80.3%), and spoon-feeding (74.1%). Infants consumed vegetables (63.2%) and fruit (53.9%) more frequently than grain foods (49.5%), milk and milk products (38.6%), and meat and protein-rich foods (31.8%). Most caregivers avoided inappropriate beverages (93.9%) and adding salt (76.5%) and sugar (90.6%). Our findings indicated that while most infants met the recommendations for the introduction of appropriate solid foods, the prevalence of exclusive breastfeeding could be improved, indicating that New Zealand families may need more support.
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Aleitamento Materno , Alimentos Infantis , Feminino , Humanos , Lactente , Dieta , Fenômenos Fisiológicos da Nutrição do Lactente , Nova Zelândia , Estudos Multicêntricos como Assunto , Estudos Observacionais como AssuntoRESUMO
BACKGROUND: The complementary feeding period is a time of unparalleled dietary change for every human, during which the diet changes from one that is 100% milk to one that resembles the usual diet of the wider family in less than a year. Despite this major dietary shift, we know relatively little about food and nutrient intake in infants worldwide and virtually nothing about the impact of baby food "pouches" and "baby-led weaning" (BLW), which are infant feeding approaches that are becoming increasingly popular. Pouches are squeezable containers with a plastic spout that have great appeal for parents, as evidenced by their extraordinary market share worldwide. BLW is an alternative approach to introducing solids that promotes infant self-feeding of whole foods rather than being fed purées, and is popular and widely advocated on social media. The nutritional and health impacts of these novel methods of infant feeding have not yet been determined. OBJECTIVE: The aim of the First Foods New Zealand study is to determine the iron status, growth, food and nutrient intakes, breast milk intake, eating and feeding behaviors, dental health, oral motor skills, and choking risk of New Zealand infants in general and those who are using pouches or BLW compared with those who are not. METHODS: Dietary intake (two 24-hour recalls supplemented with food photographs), iron status (hemoglobin, plasma ferritin, and soluble transferrin receptor), weight status (BMI), food pouch use and extent of BLW (questionnaire), breast milk intake (deuterium oxide "dose-to-mother" technique), eating and feeding behaviors (questionnaires and video recording of an evening meal), dental health (photographs of upper and lower teeth for counting of caries and developmental defects of enamel), oral motor skills (questionnaires), and choking risk (questionnaire) will be assessed in 625 infants aged 7.0 to 9.9 months. Propensity score matching will be used to address bias caused by differences in demographics between groups so that the results more closely represent a potential causal effect. RESULTS: This observational study has full ethical approval from the Health and Disability Ethics Committees New Zealand (19/STH/151) and was funded in May 2019 by the Health Research Council (HRC) of New Zealand (grant 19/172). Data collection commenced in July 2020, and the first results are expected to be submitted for publication in 2022. CONCLUSIONS: This large study will provide much needed data on the implications for nutritional intake and health with the use of baby food pouches and BLW in infancy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12620000459921; http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379436. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/29048.
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Dietary recommendations during pregnancy and lactation have become increasingly complex, and sources of information more numerous but not always reliable, potentially causing confusion and unsafe choices. Women were recruited during pregnancy or within six months postpartum and completed questionnaires on dietary choices, food safety, and sources of nutrition information. Women (n = 458) from around New Zealand participated in the study. They consumed a wide range of foods and beverages and reported various dietary changes. In pregnancy, women commonly avoided alcohol (92%), raw milk products (86%), and raw, smoked, or pre-cooked seafood and fish (84%), and made changes due to food safety concerns. Influential advice was acquired from a range of sources including midwives (37%) and the New Zealand pregnancy and breastfeeding guidelines (25%) during pregnancy. Food avoidance was less common in lactation. However, fewer women consumed milk products during lactation (64%) than pregnancy (93%). Potentially unreliable sources were used more frequently in lactation including alternative health practitioners (26%) and family or friends (12%), and dietary changes were often made in response to infant symptoms without supporting evidence. This study highlighted a need for good communication of evidence-based recommendations to women, especially during lactation.
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Aleitamento Materno , Dieta , Lactação , Adulto , Estudos Transversais , Comportamento Alimentar , Feminino , Alimentos , Inocuidade dos Alimentos , Humanos , Nova Zelândia , Estado Nutricional , Período Pós-Parto , Gravidez , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The efficacy and high barrier to resistance of darunavir have been demonstrated across diverse populations with HIV-1 infection. OBJECTIVE: To evaluate post-baseline resistance among patients in studies of once-daily (QD) darunavir-based regimens and formulations. METHODS: The analysis included treatment-naïve and virologically failing or suppressed patients from 10 phase 2/3 studies (48-192 weeks in duration) of boosted darunavir 800 mg QD-based regimens. Three were phase 3 studies of the QD darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen. Post-baseline resistance was evaluated upon protocol-defined virologic failure (PDVF). Resistance-associated mutations (RAMs) were identified using International Antiviral Society-USA mutation lists. Phenotypic analyses varied across studies. RESULTS: Overall, 250 of 3635 patients in the analysis met PDVF criteria; 205 had post-baseline genotypes/phenotypes. In total, four (0.1%) patients developed (or had identified) ≥1 darunavir and/or primary protease inhibitor (PI) RAM; only one (<0.1%) patient (with prior lopinavir virologic failure) lost darunavir phenotypic susceptibility. Among 3317 patients using nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs; mostly emtricitabine and tenofovir), 13 (0.4%) had ≥1 N(t)RTI RAM (10 with M184I/V). Among patients receiving D/C/F/TAF (n = 1949), none had post-baseline darunavir, primary PI, or tenofovir RAMs; only two (0.1%) patients developed an emtricitabine RAM, M184V/I. CONCLUSIONS: Across a large, diverse population using darunavir 800 mg QD-based regimens and formulations, resistance development remains rare. After clinical trials that span >10 years, loss of phenotypic susceptibility to darunavir was only observed once in a PI-experienced patient and has never been observed in treatment-naïve patients, treatment-experienced PI-naïve patients, or treatment-experienced virologically suppressed patients.
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Fármacos Anti-HIV/uso terapêutico , Ensaios Clínicos como Assunto , Darunavir/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Interpretação Estatística de Dados , Esquema de Medicação , Humanos , Comprimidos , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917). OBJECTIVE: To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (AMBER: viral load [VL], CD4+ count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance; EMERALD: prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent). METHODS: Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96. Efficacy endpoints were percentage cumulative confirmed VL ≥50 copies/mL (virologic rebound; EMERALD), and VL <50 (virologic response), or ≥50 copies/mL (VF) (FDA snapshot; both trials). RESULTS: D/C/F/TAF demonstrated high Week 96 virologic responses (AMBER: 85% [308/362]; EMERALD: 91% [692/763]) and low VF rates (AMBER: 6% [20/362]; EMERALD: 1% [9/763]). In EMERALD, D/C/F/TAF showed low virologic rebound cumulative through Week 96 (3% [24/763]). Results were consistent across subgroups, including prior antiretroviral experience in EMERALD. No darunavir, primary PI, or tenofovir resistance-associated mutations were observed post-baseline. Study-drug-related serious adverse events (AEs) and AE-related discontinuations were <1% and 2%, respectively (both D/C/F/TAF arms), and similar across subgroups. eGFRcyst and bone mineral density improved or were stable and lipids increased through Week 96 across demographic subgroups, with small changes in total-cholesterol/HDL-cholesterol ratio. CONCLUSIONS: D/C/F/TAF was effective with a high barrier to resistance and bone/renal safety benefits, regardless of demographic or clinical characteristics for treatment-naïve and treatment-experienced, virologically-suppressed adults.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adulto , Alanina , Fármacos Anti-HIV/efeitos adversos , Cobicistat , Darunavir/efeitos adversos , Emtricitabina , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Pessoa de Meia-Idade , Comprimidos/farmacologia , Comprimidos/uso terapêutico , Tenofovir/análogos & derivadosRESUMO
Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL <50 copies/mL) in EMERALD. Through week 48 across both studies, no darunavir, primary PI, or tenofovir resistance-associated mutations (RAMs) were observed in HIV-1 viruses of 1,125 participants receiving D/C/F/TAF or 629 receiving boosted darunavir plus emtricitabine/tenofovir-disoproxil-fumarate. In AMBER, the nucleos(t)ide analog reverse transcriptase inhibitor (N(t)RTI) RAM M184I/V was identified in HIV-1 of one participant during D/C/F/TAF treatment. M184V was detected pretreatment as a minority variant (9%). In EMERALD, in participants with prior VF and genoarchive data (N = 140; 98 D/C/F/TAF and 42 control), 4% had viruses with darunavir RAMs, 38% with emtricitabine RAMs, mainly at position 184 (41% not fully susceptible to emtricitabine), 4% with tenofovir RAMs, and 21% ≥ 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response.
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Adenina/análogos & derivados , Cobicistat/administração & dosagem , Darunavir/administração & dosagem , Farmacorresistência Viral , Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Adenina/administração & dosagem , Adulto , Alanina , Fármacos Anti-HIV/administração & dosagem , Esquema de Medicação , Combinação de Medicamentos , Infecções por HIV/epidemiologia , HIV-1/efeitos dos fármacos , Humanos , Inibidores da Transcriptase Reversa/administração & dosagem , Comprimidos/administração & dosagem , Tenofovir/análogos & derivados , Carga Viral/efeitos dos fármacosRESUMO
Objective: Evaluation of provider compliance with antiretroviral (ARV) treatment guidelines and patient adherence to ARVs is important for HIV care quality assessment; however, there are few current real-world data for guideline compliance and ARV adherence in the US. This study evaluated provider compliance with US Department of Health and Human Services (DHHS) guidelines and patient adherence to ARVs in a US population of patients with HIV.Methods: This was a retrospective claims study of adults with HIV-1 receiving ARV treatment between January 2010-December 2014. Follow-up began at first ARV treatment and ended at health plan disenrollment or study end. ARV regimens for treatment-naïve patients were categorized as "preferred/recommended", "alternative", or "non-preferred/recommended/alternative" according to DHHS guidelines. ARV adherence was evaluated using proportion of days covered (PDC) and medication possession ratio (MPR).Results: The analysis included 25,320 patients (84.4% male, mean age 45.3 years) and 39,071 regimens. Preferred/recommended regimens were most common during each study year, but the proportion of non-preferred/recommended/alternative regimens was substantial (15.9-20.6%). Only 53.6% of patients had optimal adherence by PDC ≥0.95, and 57.9% by MPR ≥0.95. Guideline non-compliance and sub-optimal adherence were more prevalent among female vs male patients (22.6% vs 14.8% [in 2014] and 65.9% vs 53.7%, respectively).Conclusions: Provider non-compliance with DHHS guidelines and sub-optimal ARV adherence among patients with HIV remain common in real-world practice, particularly for female patients. Healthcare providers should follow the latest clinical guidelines to ensure that patients receive recommended therapy, and address non-adherence when selecting ARV regimens.
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Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Adesão à Medicação , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Qualidade da Assistência à Saúde , Estudos RetrospectivosRESUMO
Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once-daily single-tablet regimen for the treatment of human immunodeficiency virus-1 infection. Different administration modalities for the D/C/F/TAF fixed-dose combination tablet were explored in this phase 1 randomized, open-label, 3-period, 3-treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference). Pharmacokinetic parameters (noncompartmental analysis; logarithm-transformed) for each component were compared using linear mixed-effects modeling. For the split versus whole tablet, the bioavailabilities (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUClast ]) of each D/C/F/TAF component were comparable. For the crushed versus whole tablet, the bioavailabilities of darunavir, cobicistat, and emtricitabine were comparable, except for a 17% decrease in emtricitabine Cmax ; the relative bioavailability of tenofovir alafenamide decreased by 29% and 19% for Cmax and AUClast , respectively. All intakes were safe and generally well tolerated. In summary, there was no clinically relevant impact on the bioavailability of D/C/F/TAF components when administered as a split tablet compared with a tablet swallowed whole. Administration of a crushed tablet resulted in a modest decrease in tenofovir alafenamide bioavailability; the clinical relevance of this change has not been assessed but is expected to be minimal based on the wide therapeutic window for this agent.
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Adenina/análogos & derivados , Cobicistat/farmacocinética , Darunavir/farmacocinética , Emtricitabina/farmacocinética , Adenina/administração & dosagem , Adenina/farmacocinética , Adulto , Alanina , Disponibilidade Biológica , Cobicistat/administração & dosagem , Estudos Cross-Over , Darunavir/administração & dosagem , Combinação de Medicamentos , Emtricitabina/administração & dosagem , Feminino , Voluntários Saudáveis , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Comprimidos , Tenofovir/análogos & derivados , Adulto JovemRESUMO
Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10â¯mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VLâ¯<â¯50 copies/mL (virologic suppression) and ≥50 copies/mL (VF) (FDA-snapshot analysis). Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52-96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF.
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Fármacos Anti-HIV/uso terapêutico , Combinação de Medicamentos , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Idoso , Alanina , Cobicistat/uso terapêutico , Darunavir/uso terapêutico , Emtricitabina/uso terapêutico , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/uso terapêutico , Feminino , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Resposta Viral Sustentada , Comprimidos/uso terapêutico , Tenofovir/análogos & derivados , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
Background: The once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is approved for the treatment of HIV-1 infection. The 48-week efficacy and safety of D/C/F/TAF versus darunavir/cobicistat + emtricitabine/tenofovir disoproxil fumarate (control) in treatment-naïve adults were demonstrated in the phase 3 AMBER study. Objective: To describe AMBER outcomes across patient subgroups based on demographic and clinical characteristics at baseline. Methods: AMBER patients had viral load (VL) ≥1000 copies/mL, CD4+ cell count >50 cells/µL, and genotypic susceptibility to darunavir, emtricitabine, and tenofovir. Primary endpoint was the proportion of patients with virologic response (VL <50 copies/mL; FDA snapshot). Safety was assessed by adverse events, estimated glomerular filtration rate (cystatin C; eGFRcystC), and bone mineral density. Outcomes were assessed by age (≤/>50 years), gender, race (black/non-black), baseline VL (≤/>100,000 copies/mL), baseline CD4+ cell count (≥200 cells/µL), and baseline WHO clinical stage of HIV infection (1/2). Results: For the 725 AMBER patients (D/C/F/TAF: 362; control: 363), virologic response rates at week 48 were similar with D/C/F/TAF (91%) and control (88%), and this was consistent across all subgroups. Adverse event rates were similar in both arms, although numerically higher among patients >50 years and women, relative to their comparator groups, regardless of treatment arm (notably, sample sizes were small for patients >50 years and women). Improvements in eGFRcystC and stable bone mineral density were observed with D/C/F/TAF overall, and results were generally consistent across subgroups. Conclusions: For treatment-naïve patients in AMBER, initiating therapy with the D/C/F/TAF single-tablet regimen was an effective and well-tolerated option, regardless of demographic or clinical characteristics.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Cobicistat/administração & dosagem , Darunavir/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adolescente , Adulto , Idoso , Alanina , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Cobicistat/efeitos adversos , Darunavir/efeitos adversos , Método Duplo-Cego , Emtricitabina/efeitos adversos , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Carga Viral/efeitos dos fármacos , Adulto JovemRESUMO
Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-)-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-)-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-)-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-)-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-)-opioid agonists suppress pain.
Assuntos
Naloxona/uso terapêutico , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Dor , Receptor 4 Toll-Like/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Biomarcadores/metabolismo , Linhagem Celular , Humanos , Injeções Espinhais , Masculino , Microglia/metabolismo , Naloxona/metabolismo , Naloxona/farmacologia , Naltrexona/metabolismo , Naltrexona/farmacologia , Antagonistas de Entorpecentes/metabolismo , Antagonistas de Entorpecentes/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/antagonistas & inibidoresRESUMO
INTRODUCTION: Physiologic changes during pregnancy may impact the pharmacokinetics of drugs. In addition, efficacy and safety/tolerability concerns have been identified for some antiretroviral agents. METHODS: Human immunodeficiency virus (HIV)-1-infected pregnant women (18-26 weeks gestation) receiving the non-nucleoside reverse transcriptase inhibitor rilpivirine 25 mg once daily were enrolled in this phase 3b, open-label study examining the impact of pregnancy on the pharmacokinetics of rilpivirine when it is given in combination with other antiretroviral agents. Blood samples (collected over the 24-h dosing interval) to assess total and unbound rilpivirine plasma concentrations were obtained during the second and third trimesters (24-28 and 34-38 weeks gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters were derived using noncompartmental analysis and compared (pregnancy versus postpartum) using linear mixed effects modeling. Antiviral and immunologic response and safety were assessed. RESULTS: Nineteen women were enrolled; 15 had evaluable pharmacokinetic results. Total rilpivirine exposure was 29-31% lower during pregnancy versus postpartum; differences were less pronounced for unbound (pharmacodynamically active) rilpivirine. At study entry, 12/19 (63.2%) women were virologically suppressed; 10/12 (83.3%) women were suppressed at the postpartum visit. Twelve infants were born to the 12 women who completed the study (7 discontinued); no perinatal viral transmission was observed among 10 infants with available data. Rilpivirine was generally safe and well tolerated in women and infants exposed in utero. CONCLUSION: Despite decreased rilpivirine exposure during pregnancy, treatment was effective in preventing mother-to-child transmission and suppressing HIV-1 RNA in pregnant women. Results suggest that rilpivirine 25 mg once daily, as part of individualized combination antiretroviral therapy, may be an appropriate option for HIV-1-infected pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT00855335.
RESUMO
The emergence and transmission of antiretroviral drug resistance have been and remain a concern among people living with human immunodeficiency virus (HIV)-1 infection. The protease inhibitor (PI) darunavir has been approved for use in the United States for more than 10 years and has demonstrated a high barrier to resistance. Previous analyses identified significant reductions in the prevalence of samples with darunavir resistance-associated mutations (RAMs) and with phenotypic resistance to darunavir and other PIs between 2006 and 2012. This analysis extends those findings by evaluating darunavir and PI resistance among clinical samples submitted for routine drug resistance testing (combined genotyping and phenotyping) in the United States from 2010 to 2017. Frequencies of 11 darunavir and 23 primary PI RAMs, and phenotypic susceptibility, were assessed yearly among all samples and in a subset of samples with distinct phenotypic resistance to one or more PIs. Among all samples (N = 60,760), the proportion with 0 darunavir RAMs was 91.7% in 2010 and 95.8% in 2017. The proportions of all samples with phenotypic susceptibility to darunavir, atazanavir, and lopinavir were, respectively, 97.4%, 94.2%, and 94.7% in 2010 and 98.6%, 97.7%, and 97.5% in 2017. Among the 4,799 samples with phenotypic resistance to one or more PIs, the proportions with phenotypic susceptibility to darunavir, atazanavir, and lopinavir were, respectively, 73.3%, 41.5%, and 46.0% in 2010 and 70.7%, 53.7%, and 48.8% in 2017. The prevalence of darunavir RAMs among commercially tested HIV-1 samples remained low and generally stable from 2010 to 2017, and high proportions showed phenotypic darunavir susceptibility.
Assuntos
Darunavir/farmacologia , Farmacorresistência Viral/genética , Inibidores da Protease de HIV/farmacologia , Mutação , História do Século XXI , Humanos , Concentração Inibidora 50 , Estados UnidosRESUMO
INTRODUCTION: We evaluated cardiovascular disease (CVD) risk associated with darunavir treatment and examined the demographic/clinical characteristics of darunavir users based on data from Janssen-sponsored clinical trials, post-marketing pharmacovigilance databases, and administrative claims databases. METHODS: First, selected CVD events [myocardial infarction, stroke, sudden death, invasive cardiovascular procedures (coronary artery angioplasty or bypass, or carotid endarterectomy)] were analyzed in 19 Janssen-sponsored phase 2-4 studies (incidence rates estimated from pooled data; 95% confidence intervals derived from Poisson distribution). Second, analyses were conducted to identify spontaneously reported CVD events in post-marketing pharmacovigilance databases and evaluate disproportional reporting of CVD events for darunavir (using Empirical Bayesian Geometric Mean scores). Third, baseline demographic/clinical characteristics of human immunodeficiency virus-1 (HIV-1)-infected patients in general and new users of darunavir and atazanavir were explored using three US administrative claims databases. RESULTS: Among 19 Janssen-sponsored clinical trials (treatment durations ≤ 6 years), the CVD event rate (95% CI) per 1000 person-years (pooled population; n = 5713) was 6.15 (2.91-11.89), and was lower for patients who used once-daily darunavir/ritonavir 800/100 mg [0.71 (0.16-3.05); n = 1326] versus twice-daily darunavir/ritonavir 600/100 mg [9.21 (4.94-16.04); n = 3058]. Trend analysis of post-marketing pharmacovigilance data showed that cumulative CVD event reporting rates for darunavir users (any dose) generally declined over time. Spontaneously reported CVD events were not disproportionately reported with darunavir versus other protease inhibitors. Compared with the general HIV-1-infected population and atazanavir users, higher proportions of darunavir users were male, older, and had comorbidities associated with CVD risk based on results from US administrative claims databases. CONCLUSIONS: This comprehensive review of Janssen-sponsored clinical trial, post-marketing, and epidemiological data does not suggest that CVD should be considered an important risk for users of darunavir.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Darunavir/efeitos adversos , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Darunavir/uso terapêutico , Feminino , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
In the original publication of the article, Table 2 has been published incorrectly.
RESUMO
BACKGROUND: An aging HIV-1-infected population warrants examination of the acceptability of individual antiretroviral regimens. In a previous study of ritonavir-boosted darunavir (ARTEMIS), similar safety/efficacy profiles were observed in younger (≤45 years) and older (>45 years) HIV-1-infected subjects. OBJECTIVE: To evaluate safety and efficacy outcomes in HIV-1-infected younger versus older subjects treated with cobicistat-boosted darunavir. METHOD: In a 48-week, phase 3b, open-label trial, HIV-1-infected adults were administered darunavir 800 mg and cobicistat 150 mg once-daily with 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs). Post hoc analyses examined safety and efficacy outcomes in subjects ≤45 and >45 years. RESULTS: Of 313 subjects, 76% were ≤45 years (median [range] age, 31 [18-45]) and 24% were >45 years (49 [46-72]). Baseline median (range) viral loads were 4.75 (2.6-6.8) and 4.83 (2.7-7.0) log10 copies/mL, and CD4+ counts were 379.0 (5-1473) and 310.5 (6-757) cells/mm3 in younger and older subjects, respectively. Through Week 48, similar proportions of younger and older subjects had ≥1 adverse event (AE; 93% vs 88%), ≥1 grade 2-4 AE possibly related to study drug (13% vs 15%), and discontinued study due to AE (3% vs 3%). At Week 48, 82% of younger and 78% of older subjects had viral load <50 copies/mL (95% CI of the difference: -7.4% to 13.8%). A higher proportion of older versus younger subjects took >4 concomitant medications during the study (69% vs 57%). CONCLUSION: Safety and efficacy profiles of cobicistat-boosted darunavir with 2 N(t)RTIs were similar in HIV-1-infected subjects ≤45 and >45 years.