Provamos a existência de soluções periódicas de algumas equações diferenciais funcionais com retardamento sujeitas a condições de impulsos de auto-sustentação. Devido aos impulsos, soluções exibem descontinuidades de primeira espécie e isso força considerarmos espaços de fase mais gerais que C([-r,0],Rn). Mostramos que soluções periódicas podem emanar da origem através de bifurcações locais de Hopf. Também estabelecemos um teorema de existência de soluções periódicas lentamente espiralantes. Esse teorema é obtido combinando-se a condição de auto-sustentação com a ejetividade da origem em relação a um operador de retorno. / We prove the existence of periodic solutions of some retarded functional differential equations subjected to impulsive self-supporting conditions. Due to the impulses, solutions exhibit discontinuites of the first kind and this forces the consideration of more general phase spaces than C([-r,0],Rn). We show that periodic solutions can emanate from the origin through local Hopf bifurcations. We also state an existence theorem for slowly spiralling periodic solutions. This theorem is accomplished by a combination of the self-supporting condition with the ejectivity of the origin with respect to a return operator.

Notre équipe à montré que les cellules de lymphome de Burkitt (LB) infectées par le variant P3HR1 du virus d’Epstein Barr (EBV) sont plus résistantes à l’apoptose que les cellules de LB EBV(-) ou infectées par la souche sauvage. Le variant P3HR1 porte une délétion de son génome à l’origine de l’expression d’une forme tronquée d’EBNA-LP (EBNA-LPt). Nous avons étudié le rôle fonctionnel d’EBNA-LPt dans les cellules de LB infectées par le variant P3HR1. Nous avons, dans un premier temps, identifié par une étude protéomique ses partenaires cellulaires et viraux. Nous avons ainsi confirmé l’interaction entre EBNA-LPt et la PP2A, déjà établie par notre équipe, et montré qu’elle forme également des complexes avec d’autres protéines impliquées dans de nombreux processus cellulaires, notamment dans l’apoptose et dans la régulation transcriptionnelle. Nous avons ensuite, par une étude du transcriptome, montré le rôle de régulateur transcriptionnel des deux formes d’EBNA-LP exprimées de façon stable dans les cellules de LB EBV(-). En effet, nous avons montré que les deux formes d’EBNA-LP sont capables de réguler l’expression des gènes cellulaires indépendamment du contexte viral. Certains de ces gènes sont communs aux deux formes d’EBNA-LP, d’autres sont spécifiques de chaque forme. Nous avons constaté que le domaine Y1Y2 est indispensable à la surexpression, par EBNA-LP, du gène cellulaire codant pour la protéine ID1 qui est impliquée dans la stabilisation de la LMP1 et dans l’immortalisation cellulaire. Nous avons également remarqué que certains gènes sont régulés de la même façon en présence d’EBNA-LP seule ou dans un contexte viral complet. Enfin et pour mieux comprendre les mécanismes de résistance à l’apoptose dans les cellules de LB infectées par la souche P3HR1, nous avons élargi notre étude du transcriptome à des cellules traitées ou non par un inducteur de l’apoptose, la cycloheximide. Nos résultats préliminaires montrent que les voies de signalisation des récepteurs au TNF (TNFR1 et 2) sont rapidement et fortement induites dans les cellules sensibles alors qu’elles sont faiblement et tardivement induites dans les cellules résistantes. Cette étude montre également que la voie de signalisation JNK est probablement activée de façon très précoce dans les cellules sensibles contrairement aux cellules résistantes. / Our group has previously shown that Burkitt’s lymphoma (BL) cells infected by the P3HR1 variant of Epstein-Barr virus (EBV) are more resistant to apoptotsis than EBV (-) BL cells or cells infected by wild-type EBV. The genome of the P3HR1 variant carries a deletion responsible for the expression of a truncated form of EBNA-LP (tEBNA-LP). We studied the functional role of tEBNA-LP in BL cells infected by the P3HR1 variant. A proteomic study allow us to identify cellular and viral partners of tEBNA-LP. These results confirmed the interaction between tEBNA-LP and PP2A, already established by our group, and showed that tEBNA-LP can form complexes with other proteins involved in many cellular processes including apoptosis and regulation of transcription. We have then demonstrated by a transcriptomic study, the transcriptional regulatory role of both forms of EBNA-LP stably expressed in EBV(-) BL cell lines. Indeed, we showed that both forms of EBNA-LP can regulate the expression of cellular genes independently of viral context. Some of these genes are common to both forms of EBNA-LP, others are specific to each form. We found that Y1Y2 domaine of EBNA-LP is essential to overexpression of the cellular gene encoding ID1 protein which is involved in LMP1 stabilization and cellular mmortalization. We also noted that some genes are similarly regulated in the presence of EBNA-LP alone or in the presence of viral genome. Finally, to better undertand the mecanisms of resistance to apoptosis in BL cell lines infected by the P3HR1 variant we extended our transcriptomic analysis to cell lines treated or not with an apoptosis inducer, cycloheximide. Our preliminary results show that TNF receptors signaling pathways (TNFR1 and 2) are rapidly and strongly induced in sensitive cell lines while being weakly and belatedly induced in the resistant cell lines. This study also shows that the JNK signaling pathway is probably activated very early in the sensitive cells in contrast to resistant cell lines.

INTRODUÇÃO: 50-86% dos pacientes recidivam a hepatite autoimune (HAI) após a suspensão do tratamento imunossupressor. A manutenção da imunossupressão em longo prazo diminui o risco de recidiva, entretanto é necessário ajuste da dose/suspensão do tratamento em 10-30%, em razão do maior risco de neoplasias e infecções. O difosfato de cloroquina (CQ) é droga imunomoduladora que foi utilizada anteriormente em monoterapia para manutenção da remissão da HAI com diminuição da recidiva quando comparada com controle histórico. O objetivo desse estudo foi investigar a eficácia e segurança do CQ na manutenção da remissão em estudo duplo cego e randomizado e avaliar se há um subgrupo com maior benefício ao seu uso. METODOLOGIA: 61 pacientes com diagnóstico provável ou definitivo de HAI em remissão histológica, 90,1% HAI tipo 1; 23% com reatividade do anti-SLA/LP, 56,6% com fibrose avançada (F3/4) à inclusão no estudo, mas com doença hepática compensada, foram randomizados de forma duplo cego e aleatória para receber CQ 250 mg/d ou placebo, durante 36 meses ou até recidiva da doença. No primeiro mês a droga foi utilizada em combinação com a imunossupressão que induziu remissão; com posterior desmame semanal da prednisona, suspensão imediata da azatioprina e manutenção do CQ/placebo até 36 meses. As curvas de sobrevida livre de recidiva foram estimadas pelo método de Kaplan-Meyer e comparadas pelo teste de Log-Rank; as razões de risco e seus respectivos intervalos de confiança foram estimados por regressão simples de Cox. Na regressão múltipla foram avaliadas co-variáveis clinicamente relevantes para recidiva. Para investigar o subgrupo com maior benefício, as interações entre a droga e reatividade de autoanticorpos e perfil de HLA foram analisadas por regressão múltipla de Cox. As variáveis categóricas foram comparadas pelo teste exato de Fisher e as quantitativas pelo teste-t ou teste de Mann-Whitney. Foi considerado estatisticamente significante um valor de p < 0,05. RESULTADOS: 31 pacientes receberam CQ e 30 placebo. Não houve diferenças entre os grupos em relação aos achados clínicos, laboratoriais, histológicos e perfil de HLA. A sobrevida livre de recidiva foi significativamente maior no grupo CQ quando comparada ao placebo (59,3% X 19,9%, p=0,039). Após a suspensão da medicação ao término do estudo, houve 41,6% de recidiva no grupo CQ e 0% no placebo. Na regressão simples de Cox, os fatores associados com recidiva da HAI foram uso placebo, reatividade do anticorpo anti-SLA/LP, perfil de HLA DR3 e DR8. Na regressão múltipla, o uso de placebo (razão de risco de 2,4[IC 95%:1,05- 5,5], p=0,039) e reatividade do anticorpo anti-SLA/LP (razão de risco= 5.4 [IC 95%:1,91-15,3], p=0,002) associaram-se a maior risco de recidiva. Não foi possível definir subgrupo de maior benefício com uso de CQ no que se refere à reatividade do anti-SLA/LP ou perfil de HLA, embora a recidiva tenha ocorrido em 100% dos pacientes anti-SLA/LP(+) no grupo placebo e 50% no grupo CQ. No grupo CQ, 54,8% apresentaram efeitos colaterais, com suspensão da droga em 19,3%. Os efeitos colaterais mais comuns foram prurido e hiperpigmentação cutânea. CONCLUSÕES: O CQ reduziu com segurança o risco de recidiva de HAI, mas não foi possível definir subgrupo com maior benefício com essa medicação / INTRODUCTION: 50-86% of patients relapse autoimmune hepatitis (AIH) after immunosuppressive treatment withdrawal, with a higher risk of progression to liver cirrhosis, death due to liver disease and liver transplantation. The maintenance of long-term immunosuppression decreases the risk of relapse, however, treatment dose adjustment and/or interruption is required in 10-30%, with increased risk of neoplasias and infections. Chloroquine diphosphate (CQ) is an immunomodulatory drug used previously in monotherapy to maintain AIH remission with a decrease risk in relapse rates when compared to a historical control. The aims of this study were to investigate the efficacy and safety of CQ in the maintenance of remission in a double-blind and randomized study, and to evaluate if there is a subgroup with a greater benefit of its use. METHODS: 61 patients with probable or definitive diagnosis of AIH in histological remission, 90.1% type 1; 23% with anti-SLA / LP seropositivity, 56.6% with advanced fibrosis [F3 / 4] at inclusion in the study and with compensated liver disease were randomized double-blindly to receive either CQ 250 mg/day or placebo for 36 months or until relapse. In the first month, the drug was used in combination with the immunosuppressive regimen that induced the remission; with subsequent weekly weaning of prednisone, immediate withdrawal of azathioprine and maintenance of CQ/placebo for up to 36 months. Recurrence-free survival curves were estimated by the Kaplan-Meyer method and compared by the Log-Rank test; the hazard ratios and their respective confidence intervals were estimated by simple Cox regression. Clinically relevant covariables for relapse were re-evaluated bymultiple Cox regression. To investigate the existence of a subgroup with a greater benefit, interactions between the drug and autoantibody reactivity and HLA profile were analyzed by the Cox multiple regression. Categorical variables were compared by Fisher\'s exact test and the quantitative by the t-test or Mann- Whitney test. A p value of < 0.05 was considered statistically significant. RESULTS: 31 patients received CQ and 30 placebo. There were no differences between the two groups in relation to clinical, laboratory, histological and HLA profiles. Relapse-free survival was significantly higher in the CQ group when compared to placebo (59.3% X 19.9%, p=0.039). After antimalarial withdrawal at the end of the study, there was 41.6% relapse in the CQ group and 0% in the placebo. In the Cox simple regression, factors associated with AIH relapse were placebo use, anti-SLA/LP seropositivity, and HLA DR3 and DR8 profiles. In multiple regression, placebo use (Hazard Ratio = 2.4 [95% CI: 1.05-5.5], p = 0.039) and anti-SLA/LP seropositivity (Hazard Ratio = 5.4 [95% CI: 1.91-15.3], p = 0.002) were associated with a higher risk of relapse. It was not possible to define a subgroup with a greater benefit of CQ with respect to anti-SLA/LP positivity or HLA profile, although all anti-SLA/LP(+) patients in placebo group relapsed, compared to 50% in CQ group. In the CQ group, 54.8% had side effects, but 19.3% had drug withdrawal. The most common side effects were pruritus and cutaneous hyperpigmentation. CONCLUSIONS: Chloroquine safely reduced the risk of relapse of AIH, but it was not possible to define a subgroup with greater benefit with medication use

Nesse trabalho, estudamos a equação de Schrödinger não-linear com uma função potencial delta atrativa. As soluções para essa equação tem uma componente localizada e uma dispersiva. Além de estudar o comportamento das soluções dessa equação em espaços de Sobolev clássicos, mostramos algumas propriedades do grupo unitário em espaços Lp, L2 com peso, Sobolev com peso e assim obtemos alguns resultados de boa colocação local e global das soluções. O ponto central desta tese é mostrarmos a existência de uma variedade invariante centro que irá consistir de órbitas periódicas no tempo. / In this work, we study the nonlinear Schrodinger equation with an attractive delta function potential.The solutions to this equation have a localized and a dispersive component. In addition to studying the behavior of solutions of this equation in classical Sobolev space, we show some properties for the unitary group in Lp, weighted L2 and Sobolev spaces and so we get some results of local and global well-posedness of solutions. The central theme this thesis is to show the existence of a center invariant manifold, which will consist of time-periodic orbits.

The aim of this paper is to investigate the known nonuniform version of Esseen's inequality in the Lp-metric, to get a numerical bound for the appearing constant L. For a long time the results given by several authors constate the impossibility of a nonuniform estimation in the most interesting case δ=1, because the effect L=L(δ)=O(1/(1-δ)), δ->1-0, was observed, where 2+δ, 0<δ<1, is the order of the assumed moments of the considered independent random variables X_k, k=1,2,...,n. Again making use of the method of conjugated distributions, we improve the well-known technique to show in the most interesting case δ=1 the finiteness of the absolute constant L and to prove L=L(1)=<127,74*7,31^(1/p), p>1. In the case 0<δ<1 we only give the analytical structure of L but omit numerical calculations. Finally an example on normal approximation of sums of l_2-valued random elements demonstrates the application of the nonuniform mean central limit bounds obtained here. / Das Anliegen dieses Artikels besteht in der Untersuchung einer bekannten Variante der Esseen'schen Ungleichung in Form einer ungleichmäßigen Fehlerabschätzung in der Lp-Metrik mit dem Ziel, eine numerische Abschätzung für die auftretende absolute Konstante L zu erhalten. Längere Zeit erweckten die Ergebnisse, die von verschiedenen Autoren angegeben wurden, den Eindruck, dass die ungleichmäßige Fehlerabschätzung im interessantesten Fall δ=1 nicht möglich wäre, weil auf Grund der geführten Beweisschritte der Einfluss von δ auf L in der Form L=L(δ)=O(1/(1-δ)), δ->1-0, beobachtet wurde, wobei 2+δ, 0<δ<1, die Ordnung der vorausgesetzten Momente der betrachteten unabhängigen Zufallsgrößen X_k, k=1,2,...,n, angibt. Erneut wird die Methode der konjugierten Verteilungen angewendet und die gut bekannte Beweistechnik verbessert, um im interessantesten Fall δ=1 die Endlichkeit der absoluten Konstanten L nachzuweisen und um zu zeigen, dass L=L(1)=<127,74*7,31^(1/p), p>1, gilt. Im Fall 0<δ<1 wird nur die analytische Struktur von L herausgearbeitet, jedoch ohne numerische Berechnungen. Schließlich wird mit einem Beispiel zur Normalapproximation von Summen l_2-wertigen Zufallselementen die Anwendung der gewichteten Fehlerabschätzung im globalen zentralen Grenzwertsatz demonstriert.

Malaria is currently a huge treat worldwide, as far as infections are concerned, and is responsible for thousands of deaths per annum. The dilemma associated with the development of anti–malarial drug resistance over the past few decades should be addressed as a matter of urgency. Novel drug delivery systems should be developed in order to employ new and existing anti–malarial drugs in the treatment and management of malaria. The aim of these delivery systems should include an improvement in the efficacy, specificity, acceptability and therapeutic index of anti–malarial drugs. Previous studies have suggested that liposomes have the ability to encapsulate, protect and to promote the sustained release of anti–malarial drugs. Two liposome formulations, namely liposomes and chloroquine entrapped in liposomes, were formulated during this thesis and evaluated by conducting a stability study and an in vitro study with the main focus on cell viability. The stability study consisted of a series of stability tests regarding the stability of nine liposome and nine chloroquine entrapped in liposome formulations over a period of twelve weeks. The in vitro study included three assays such as a reactive oxygen species assay, a lipid peroxidation assay and a hemolysis assay. The aims of these studies included the manufacturing of liposomes, the incorporation of chloroquine into liposomes, the determination of the stability of the formulations as well as the evaluation of the possible in vitro toxicity of liposomes. Results obtained from these studies revealed that liposomes remained more stable over the stability study period in comparison to chloroquine entrapped in liposomes. The entrapment of chloroquine within liposomes was possible, although the initial entrapment efficiency (%) of 14.55 % was much too low. The production of reactive oxygen species occurred to a small extent in the red blood cells and the infected red blood cells. Equal amounts of reactive oxygen species (%) was observed within both the red blood cells and the infected red blood cells with a maximum value of 23.27 % in the presence of the chloroquine entrapped in liposomes at varying concentrations. Red blood cells experienced the highest degree of lipid peroxidation (%) in the presence of chloroquine, at varying concentrations, entrapped in liposomes. The maximum amount of lipid peroxidation (%) was 79.61 %. No significant degree of hemolysis (%) was observed in the red blood cells neither in the presence of the liposomes nor in the presence of the chloroquine entrapped in liposomes at varying concentrations. It can be concluded that liposomes are a more stable formulation and have less toxic effects on red blood cells and infected red blood cells in comparison to the chloroquine entrapped in liposome formulations. Future studies should investigate the possibility of a more stable and less toxic chloroquine entrapped in liposome formulation. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Malaria is currently a huge treat worldwide, as far as infections are concerned, and is responsible for thousands of deaths per annum. The dilemma associated with the development of anti–malarial drug resistance over the past few decades should be addressed as a matter of urgency. Novel drug delivery systems should be developed in order to employ new and existing anti–malarial drugs in the treatment and management of malaria. The aim of these delivery systems should include an improvement in the efficacy, specificity, acceptability and therapeutic index of anti–malarial drugs. Previous studies have suggested that liposomes have the ability to encapsulate, protect and to promote the sustained release of anti–malarial drugs. Two liposome formulations, namely liposomes and chloroquine entrapped in liposomes, were formulated during this thesis and evaluated by conducting a stability study and an in vitro study with the main focus on cell viability. The stability study consisted of a series of stability tests regarding the stability of nine liposome and nine chloroquine entrapped in liposome formulations over a period of twelve weeks. The in vitro study included three assays such as a reactive oxygen species assay, a lipid peroxidation assay and a hemolysis assay. The aims of these studies included the manufacturing of liposomes, the incorporation of chloroquine into liposomes, the determination of the stability of the formulations as well as the evaluation of the possible in vitro toxicity of liposomes. Results obtained from these studies revealed that liposomes remained more stable over the stability study period in comparison to chloroquine entrapped in liposomes. The entrapment of chloroquine within liposomes was possible, although the initial entrapment efficiency (%) of 14.55 % was much too low. The production of reactive oxygen species occurred to a small extent in the red blood cells and the infected red blood cells. Equal amounts of reactive oxygen species (%) was observed within both the red blood cells and the infected red blood cells with a maximum value of 23.27 % in the presence of the chloroquine entrapped in liposomes at varying concentrations. Red blood cells experienced the highest degree of lipid peroxidation (%) in the presence of chloroquine, at varying concentrations, entrapped in liposomes. The maximum amount of lipid peroxidation (%) was 79.61 %. No significant degree of hemolysis (%) was observed in the red blood cells neither in the presence of the liposomes nor in the presence of the chloroquine entrapped in liposomes at varying concentrations. It can be concluded that liposomes are a more stable formulation and have less toxic effects on red blood cells and infected red blood cells in comparison to the chloroquine entrapped in liposome formulations. Future studies should investigate the possibility of a more stable and less toxic chloroquine entrapped in liposome formulation. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Le lycée professionnel accueille des adolescents qui ont rencontré des difficultés au collège et sont en rupture avec le cheminement dit « normal ». Adolescents confrontés, non pas à une, mais à des situations d’échec, ils arrivent souvent dans ces établissements en disant d’eux-mêmes « je suis nul (le), je n’y arriverai jamais ». Se pose donc la question des stratégies pédagogiques à mettre en œuvre pour réengager ces élèves dans un processus de formation. L’hypothèse centrale de cette recherche est que les enseignants de ces établissements scolaires visent, dans leurs pratiques pédagogiques, à restructurer à la fois l’estime de soi et le sentiment d’efficacité personnelle de leurs élèves afin de les remobiliser et de les réengager sur la voie de la réussite scolaire.Une première recherche par entretiens a été menée auprès de vingt neuf professeurs de lycées professionnels. Les pratiques pédagogiques qu’ils déclarent élaborer confirment notre hypothèse.Cette étude est complétée par une enquête par questionnaires réalisée auprès de deux cent soixante cinq élèves de sections d’esthétique, coiffure, maintenance des équipements industriels (MEI) et métiers de la production mécanique informatisée (MPMI), effectuée en octobre 2007 et mai 2008. Les résultats montrent qu’estime de soi et sentiment d’efficacité personnelle sont relativement mobilisés. / French vocational schools provide education to pupils, aged 16 to 19. These pupils met difficulties in their studies and had to face a succession of failures. They have split with the ordinary process of education. They regularly say about themselves « I’m not worth, I’ll never get with it ».The hypothesis of this research was that the teachers who welcome these teenagers have to enhance their self-esteem and self-efficacy in order to make them able to accept new learnings and to feel successfull at school. In a first qualitative study, we asked twenty nine teachers the way they worked with this population of pupils. What they say about the strategies they use confirms our hypothesis.This study was completed by a quantitative enquiry. 265 boys and girls were tested twice, in october 2007 and may 2008 in order to observe the evolution in self-esteem and self-efficacy. The results are not totally convincing, particularly due to the small number of boys of the study, and even if a majority of them improved in self-esteem and self-efficacy.

Provamos a existência de soluções periódicas de algumas equações diferenciais funcionais com retardamento sujeitas a condições de impulsos de auto-sustentação. Devido aos impulsos, soluções exibem descontinuidades de primeira espécie e isso força considerarmos espaços de fase mais gerais que C([-r,0],Rn). Mostramos que soluções periódicas podem emanar da origem através de bifurcações locais de Hopf. Também estabelecemos um teorema de existência de soluções periódicas lentamente espiralantes. Esse teorema é obtido combinando-se a condição de auto-sustentação com a ejetividade da origem em relação a um operador de retorno. / We prove the existence of periodic solutions of some retarded functional differential equations subjected to impulsive self-supporting conditions. Due to the impulses, solutions exhibit discontinuites of the first kind and this forces the consideration of more general phase spaces than C([-r,0],Rn). We show that periodic solutions can emanate from the origin through local Hopf bifurcations. We also state an existence theorem for slowly spiralling periodic solutions. This theorem is accomplished by a combination of the self-supporting condition with the ejectivity of the origin with respect to a return operator.

INTRODUÇÃO: 50-86% dos pacientes recidivam a hepatite autoimune (HAI) após a suspensão do tratamento imunossupressor. A manutenção da imunossupressão em longo prazo diminui o risco de recidiva, entretanto é necessário ajuste da dose/suspensão do tratamento em 10-30%, em razão do maior risco de neoplasias e infecções. O difosfato de cloroquina (CQ) é droga imunomoduladora que foi utilizada anteriormente em monoterapia para manutenção da remissão da HAI com diminuição da recidiva quando comparada com controle histórico. O objetivo desse estudo foi investigar a eficácia e segurança do CQ na manutenção da remissão em estudo duplo cego e randomizado e avaliar se há um subgrupo com maior benefício ao seu uso. METODOLOGIA: 61 pacientes com diagnóstico provável ou definitivo de HAI em remissão histológica, 90,1% HAI tipo 1; 23% com reatividade do anti-SLA/LP, 56,6% com fibrose avançada (F3/4) à inclusão no estudo, mas com doença hepática compensada, foram randomizados de forma duplo cego e aleatória para receber CQ 250 mg/d ou placebo, durante 36 meses ou até recidiva da doença. No primeiro mês a droga foi utilizada em combinação com a imunossupressão que induziu remissão; com posterior desmame semanal da prednisona, suspensão imediata da azatioprina e manutenção do CQ/placebo até 36 meses. As curvas de sobrevida livre de recidiva foram estimadas pelo método de Kaplan-Meyer e comparadas pelo teste de Log-Rank; as razões de risco e seus respectivos intervalos de confiança foram estimados por regressão simples de Cox. Na regressão múltipla foram avaliadas co-variáveis clinicamente relevantes para recidiva. Para investigar o subgrupo com maior benefício, as interações entre a droga e reatividade de autoanticorpos e perfil de HLA foram analisadas por regressão múltipla de Cox. As variáveis categóricas foram comparadas pelo teste exato de Fisher e as quantitativas pelo teste-t ou teste de Mann-Whitney. Foi considerado estatisticamente significante um valor de p < 0,05. RESULTADOS: 31 pacientes receberam CQ e 30 placebo. Não houve diferenças entre os grupos em relação aos achados clínicos, laboratoriais, histológicos e perfil de HLA. A sobrevida livre de recidiva foi significativamente maior no grupo CQ quando comparada ao placebo (59,3% X 19,9%, p=0,039). Após a suspensão da medicação ao término do estudo, houve 41,6% de recidiva no grupo CQ e 0% no placebo. Na regressão simples de Cox, os fatores associados com recidiva da HAI foram uso placebo, reatividade do anticorpo anti-SLA/LP, perfil de HLA DR3 e DR8. Na regressão múltipla, o uso de placebo (razão de risco de 2,4[IC 95%:1,05- 5,5], p=0,039) e reatividade do anticorpo anti-SLA/LP (razão de risco= 5.4 [IC 95%:1,91-15,3], p=0,002) associaram-se a maior risco de recidiva. Não foi possível definir subgrupo de maior benefício com uso de CQ no que se refere à reatividade do anti-SLA/LP ou perfil de HLA, embora a recidiva tenha ocorrido em 100% dos pacientes anti-SLA/LP(+) no grupo placebo e 50% no grupo CQ. No grupo CQ, 54,8% apresentaram efeitos colaterais, com suspensão da droga em 19,3%. Os efeitos colaterais mais comuns foram prurido e hiperpigmentação cutânea. CONCLUSÕES: O CQ reduziu com segurança o risco de recidiva de HAI, mas não foi possível definir subgrupo com maior benefício com essa medicação / INTRODUCTION: 50-86% of patients relapse autoimmune hepatitis (AIH) after immunosuppressive treatment withdrawal, with a higher risk of progression to liver cirrhosis, death due to liver disease and liver transplantation. The maintenance of long-term immunosuppression decreases the risk of relapse, however, treatment dose adjustment and/or interruption is required in 10-30%, with increased risk of neoplasias and infections. Chloroquine diphosphate (CQ) is an immunomodulatory drug used previously in monotherapy to maintain AIH remission with a decrease risk in relapse rates when compared to a historical control. The aims of this study were to investigate the efficacy and safety of CQ in the maintenance of remission in a double-blind and randomized study, and to evaluate if there is a subgroup with a greater benefit of its use. METHODS: 61 patients with probable or definitive diagnosis of AIH in histological remission, 90.1% type 1; 23% with anti-SLA / LP seropositivity, 56.6% with advanced fibrosis [F3 / 4] at inclusion in the study and with compensated liver disease were randomized double-blindly to receive either CQ 250 mg/day or placebo for 36 months or until relapse. In the first month, the drug was used in combination with the immunosuppressive regimen that induced the remission; with subsequent weekly weaning of prednisone, immediate withdrawal of azathioprine and maintenance of CQ/placebo for up to 36 months. Recurrence-free survival curves were estimated by the Kaplan-Meyer method and compared by the Log-Rank test; the hazard ratios and their respective confidence intervals were estimated by simple Cox regression. Clinically relevant covariables for relapse were re-evaluated bymultiple Cox regression. To investigate the existence of a subgroup with a greater benefit, interactions between the drug and autoantibody reactivity and HLA profile were analyzed by the Cox multiple regression. Categorical variables were compared by Fisher\'s exact test and the quantitative by the t-test or Mann- Whitney test. A p value of < 0.05 was considered statistically significant. RESULTS: 31 patients received CQ and 30 placebo. There were no differences between the two groups in relation to clinical, laboratory, histological and HLA profiles. Relapse-free survival was significantly higher in the CQ group when compared to placebo (59.3% X 19.9%, p=0.039). After antimalarial withdrawal at the end of the study, there was 41.6% relapse in the CQ group and 0% in the placebo. In the Cox simple regression, factors associated with AIH relapse were placebo use, anti-SLA/LP seropositivity, and HLA DR3 and DR8 profiles. In multiple regression, placebo use (Hazard Ratio = 2.4 [95% CI: 1.05-5.5], p = 0.039) and anti-SLA/LP seropositivity (Hazard Ratio = 5.4 [95% CI: 1.91-15.3], p = 0.002) were associated with a higher risk of relapse. It was not possible to define a subgroup with a greater benefit of CQ with respect to anti-SLA/LP positivity or HLA profile, although all anti-SLA/LP(+) patients in placebo group relapsed, compared to 50% in CQ group. In the CQ group, 54.8% had side effects, but 19.3% had drug withdrawal. The most common side effects were pruritus and cutaneous hyperpigmentation. CONCLUSIONS: Chloroquine safely reduced the risk of relapse of AIH, but it was not possible to define a subgroup with greater benefit with medication use