Background: Antiretroviral therapy (ART), notably lopinavir and nevirapine substantially reduces Human immune-deficiency virus (HIV) associated morbidity and mortality in HIVinfected children. Low concentrations of nevirapine and lopinavir have been linked to inferior virological outcomes; it is recommended that lopinavir and nevirapine concentrations are maintained above 1 mg/L and 3 mg/L, respectively, in order to maintain viral suppression. Adherence to both lopinavir and nevirapine ART, respectively has long known to be a crucial contributor to HIV treatment success. Lopinavir and nevirapine pharmacokinetics demonstrate considerable inter-individual variability, which may affect treatment outcomes. At least part of this variability may be explained by host genetic factors. Associations between human genetic variants and exposure to lopinavir and nevirapine are incompletely understood, and have not been studied in a South African paediatric population. Data in this thesis were from a clinical trial conducted at Rahima Moosa Mother and Child Hospital in Johannesburg to assess whether NVP can be re-used (Post-randomization Phase) among 323 children exposed to NVP for PMTCT if they are first suppressed on ritonavir-boosted lopinavir based regimen (Pre-randomization Phase). This thesis assessed the relationship between serial clinic visits lopinavir (Pre-and-Post-randomization) and nevirapine (Postrandomization) concentrations and/or percentage adherence(Pre-and-Post-randomization) and virological outcomes in children. Moreover, population pharmacokinetics models were used to characterise lopinavir and nevirapine parameters. From the final models parameters were derived and were used to assess the relationship between lopinavir and nevirapine pharmacokinetics and genetic polymorphism relevant to both drugs Methods: Cox proportional hazard regression modelling for multiple failure events was used to estimate the crude and adjusted hazard effect of lopinavir (Pre-and Post-randomization) and nevirapine(Post-randomization) concentrations and/or percent adherence(Pre-and Post-randomization) of viral load>400 copies/mL (Pre-randomization) and >50 copies/mL (Post-randomization), respectively. The population means and variances of lopinavir and nevirapine pharmacokinetic parameters at steady state were estimated using non-linear mixed-effects regression. The final models of lopinavir and nevirapine were used to derive individual clearances (CL/F), minimum concentrations (Cmin) and area under the concentration time curves (AUC). The associations between model-derived pharmacokinetic parameters and genotypes in selected genes relevant to lopinavir or nevirapine were explored. Results: In 237 children pre-randomization with viral loads and lopinavir concentrations, the crude and adjusted Cox models revealed significant associations between virologic failure (viral load>400 copies/mL) and both lopinavir plasma concentrations (<1/mg/L) and pretreatment height-for-age z-scores but not percent adherence. In 99 children postrandomization, lopinavir concentrations >1 mg/L reduced the risk of viremia (viral load >50 copies/mL) with about 40%, compared to children with LPV <1 mg/L. No association was found with percent adherence in this group. In 95 children on nevirapine post-randomization, nevirapine concentrations were not significantly associated with increased hazard of viremia (viral load >50 copies/mL). Similarly, there was no significant association with percent adherence in this group. Lopinavir and nevirapine pharmacokinetics were both separately best described with a one compartment models with absorption lag time and transit compartment absorption models, respectively. There was an age driven effect on lopinavir and nevirapine relative bioavailability, respectively. After adjusting for multiple testing, there was no significant association between lopinavir CL/F, Cmin and AUC and genetic polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1. CYP2B6 516G→T and CYP2B6 983T→C were associated with NVP CL/F. CYP2B6 983T→C was associated with NVP Cmin and AUC. Additionally, polymorphisms in the ABCB1 and CYP3A5 were independently associated with NVP CL/F, Cmin and AUC. Conclusions: Lopinavir concentrations <1mg/L were associated with the increased hazard of viremia (viral load >400 copies/mL or >50 copies/mL). The results suggest that lopinavir plasma concentration monitoring at a routine clinic visit may be a useful tool in identifying sub-therapeutic antiretroviral concentrations in children, and this could be used as a guide to therapeutic drug monitoring in children. There was no statistically significant association between polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1 and lopinavir pharmacokinetics. Polymorphisms in the ABCB1, CYP2B6 CYP3A4 and CYP3A5 predicted nevirapine pharmacokinetics.

Made available in DSpace on 2014-06-11T19:31:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-12-02Bitstream added on 2014-06-13T19:40:46Z : No. of bitstreams: 1 gutierrez_ma_dr_jabo.pdf: 1348720 bytes, checksum: 950c7d77602e6f460587cb09d238d462 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Objetivou-se avaliar a influência do espaçamento entre linhas e da densidade populacional sobre componentes microclimáticos e características agronômicas da cultura do milho. O experimento foi conduzido na safra 2007/2008, em condições de campo, em Latossolo Vermelho distrófico típico, textura média, A moderado, em Monte Aprazível, SP. O delineamento experimental utilizado foi o DBC, com sete tratamentos e quatro repetições, totalizando 28 unidades experimentais. Os tratamentos consistiram dos espaçamentos entre linhas de 40, 60, 80, 100, 120, 140 e 160 cm, correspondentes às densidades populacionais de 125.000, 83.300, 62.500, 50.000, 41.666, 35.714 e 31.250 plantas/ha. As variáveis microclimáticas avaliadas foram: temperatura do ar e do solo, umidade do ar e do solo, radiação fotossinteticamente ativa (RFA), atividades enzimáticas microbianas do solo (urease, fosfatase e desidrogenase). As variáveis agronômicas avaliadas foram: estatura de plantas, altura de inserção da primeira espiga, número de espigas por planta, diâmetro do colmo, acamamento e quebramento de plantas, nº de grãos na primeira espiga, massa de grãos na primeira espiga, massa de mil grãos, índice de colheita, massa seca de folhas, caules e grãos, concentração de macronutrientes e micronutrientes em folhas, caules e grãos. Com a redução do espaçamento entre linhas, de 160 a 40 cm, houve aumento da umidade do ar e do solo, da radiação fotossinteticamente ativa interceptada, do índice de área foliar, da atividade as urease no solo, da altura das plantas, da altura de inserção da primeira espiga e diminuição de diâmetro do colmo, do número de grãos por fileira, do número de grãos por espiga, da massa de mil grãos, da temperatura máxima do ar e do solo, da área foliar média e da área foliar total da planta e da massa seca de folhas e de grãos por planta... / The study aimed to evaluate the influence of row spacing and plant population on climatic components and agronomic variables of maize. The experiment was carried out in the agricultural year of 2007/2008 crop, under field conditions in a typical Oxisol, medium texture, moderate, in Monte Aprazível, SP. The experimental design was a complete randomized block, with seven treatments (row spacing) and four replications, totaling 28 experimental units. The following microenvironmental variables were evaluated: air and soil temperature, air and soil humidity, PHAR, soil microbial enzymatic activities (urease, phosphatase and dehydrogenase). The following Agronomic variables were evaluated: plant height, first ear height, number of ear per plant, stem diameter, lodging and breaking of plants, number of grains in the first spike, grain weight in the first spike, mass of thousand grain, yield index, dry mass of leaves, stems and grains, micronutrients and macronutrients in leaves, stems and grains. With the reduction in spacing, from 160 to 40 cm, observed an increase of air and soil humidity, intercepted PHAR, the leaf area index, the urease activity in soil, plant height, height insertion of the first spike and decreased stem diameter, number of kernels per row, the number of grains per spike, thousand grain mass, the maximum air and soil temperature, the average leaf area and leaf area plant and dry mass of leaves and seeds per plant. With the increased spacing of 40-100 cm we observed increase in minimum air temperature. With the increased spacing of 100-160 cm decreased the minimum air temperature. The reduction in spacing did not influence the activities of phosphatase and dehydrogenase in the soil, the number of spikes per plant, harvest index and stem dry mass. The plant height increased with increasing PAR and LAI.

Orientador: Jairo Osvaldo Cazetta / Banca: Anice Garcia / Banca: Silvelena Vanzolini Segato / Banca: Rogério Farinelli / Banca: Domingos Fornasieri Filho / Resumo: Objetivou-se avaliar a influência do espaçamento entre linhas e da densidade populacional sobre componentes microclimáticos e características agronômicas da cultura do milho. O experimento foi conduzido na safra 2007/2008, em condições de campo, em Latossolo Vermelho distrófico típico, textura média, A moderado, em Monte Aprazível, SP. O delineamento experimental utilizado foi o DBC, com sete tratamentos e quatro repetições, totalizando 28 unidades experimentais. Os tratamentos consistiram dos espaçamentos entre linhas de 40, 60, 80, 100, 120, 140 e 160 cm, correspondentes às densidades populacionais de 125.000, 83.300, 62.500, 50.000, 41.666, 35.714 e 31.250 plantas/ha. As variáveis microclimáticas avaliadas foram: temperatura do ar e do solo, umidade do ar e do solo, radiação fotossinteticamente ativa (RFA), atividades enzimáticas microbianas do solo (urease, fosfatase e desidrogenase). As variáveis agronômicas avaliadas foram: estatura de plantas, altura de inserção da primeira espiga, número de espigas por planta, diâmetro do colmo, acamamento e quebramento de plantas, nº de grãos na primeira espiga, massa de grãos na primeira espiga, massa de mil grãos, índice de colheita, massa seca de folhas, caules e grãos, concentração de macronutrientes e micronutrientes em folhas, caules e grãos. Com a redução do espaçamento entre linhas, de 160 a 40 cm, houve aumento da umidade do ar e do solo, da radiação fotossinteticamente ativa interceptada, do índice de área foliar, da atividade as urease no solo, da altura das plantas, da altura de inserção da primeira espiga e diminuição de diâmetro do colmo, do número de grãos por fileira, do número de grãos por espiga, da massa de mil grãos, da temperatura máxima do ar e do solo, da área foliar média e da área foliar total da planta e da massa seca de folhas e de grãos por planta... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The study aimed to evaluate the influence of row spacing and plant population on climatic components and agronomic variables of maize. The experiment was carried out in the agricultural year of 2007/2008 crop, under field conditions in a typical Oxisol, medium texture, moderate, in Monte Aprazível, SP. The experimental design was a complete randomized block, with seven treatments (row spacing) and four replications, totaling 28 experimental units. The following microenvironmental variables were evaluated: air and soil temperature, air and soil humidity, PHAR, soil microbial enzymatic activities (urease, phosphatase and dehydrogenase). The following Agronomic variables were evaluated: plant height, first ear height, number of ear per plant, stem diameter, lodging and breaking of plants, number of grains in the first spike, grain weight in the first spike, mass of thousand grain, yield index, dry mass of leaves, stems and grains, micronutrients and macronutrients in leaves, stems and grains. With the reduction in spacing, from 160 to 40 cm, observed an increase of air and soil humidity, intercepted PHAR, the leaf area index, the urease activity in soil, plant height, height insertion of the first spike and decreased stem diameter, number of kernels per row, the number of grains per spike, thousand grain mass, the maximum air and soil temperature, the average leaf area and leaf area plant and dry mass of leaves and seeds per plant. With the increased spacing of 40-100 cm we observed increase in minimum air temperature. With the increased spacing of 100-160 cm decreased the minimum air temperature. The reduction in spacing did not influence the activities of phosphatase and dehydrogenase in the soil, the number of spikes per plant, harvest index and stem dry mass. The plant height increased with increasing PAR and LAI. / Doutor