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Background Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy. Methods IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics. Results Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P Conclusions 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy. Clinical Trials Registration ClinicalTrials.gov, NCT02651259.

Objective(s)The short-term safety of treatment interruptions, a necessary part of cure studies, is not well established, particularly in women. We explored viral rebound kinetics and safety in a group of postpartum women discontinuing ART and compared results to men in historical interruption trials.DesignProspective evaluation of time to virologic rebound.MethodsOne thousand and seventy-six asymptomatic, virally suppressed, postpartum women living with HIV enrolled in the PROMISE trial with baseline CD4 cell counts at least 350 cells/μl underwent antiretroviral treatment (ART) discontinuation. Proportion with virologic suppression at weeks 4 and 12 were compared with participants in ACTG treatment interruption trials (91% male population).ResultsIn PROMISE, using interval censored methods, the estimated median time to HIV viral rebound was 2 weeks. An estimated 6% of women would remain virally suppressed at 30 weeks. Of those who had viral rebound by 30 weeks (N = 993), less than 4% experienced grade 3 or higher laboratory events, and 1% experienced WHO stage 2 or higher clinical events. Overall, less than 1% of participants progressed from WHO Stage 1 to Stage 2 or higher after discontinuation of ART, and 3.9% experienced a decline in CD4 cell count to less than 350 cells/μl or local treatment guidelines. A significantly higher proportion of women in PROMISE (25.4%) were virologically suppressed (

Introduction Fibromyalgia (FM) is consistently associated with fatigue, sleep disturbances, morning stiffness, and anxiety and depression, affecting physical capacities and skills and thereby reducing quality of life. The aim of this study was to compare the effects of water-based and land-based therapies as an adjuvant treatment for women with FM in relation to quality of life and physical aspects. Methods FM women were randomized into a water-based exercise group (WG) and land-based exercise group (LG). The interventions were conducted for 8 weeks, three times a week, and each therapy session had a 60-min duration. Evaluations were performed before and after intervention using the Fibromyalgia Impact Questionnaire, the Visual Analogue Scale, the number of tender points (TPs), and the Wells bench sit and reach test score. Results Both interventions produced significantly positive clinical effects in most aspects evaluated. However, only WG obtained significant improvements for the variables functional capacity, number of TPs, and flexibility. Conclusions The findings suggest that water-based exercise is effective as an adjuvant FM treatment, including FM-related physical and psychological health aspects.

O presente trabalho tem como objetivo fazer uma análise a respeito da atualização do documento das Nações Unidas, atualmente conhecido como “Regras de Mandela”, verificando a sua aplicabilidade no sistema prisional brasileiro. Da mesma forma, o artigo busca observar a necessidade do cumprimento não apenas do documento da ONU, como também dos direitos fundamentais já previstos nas leis do país. Por meio de uma análise conjunta da legislação brasileira e do tratado internacional, percebe-se que o sistema carcerário no Brasil se encontra falido, devido às inúmeras violações aos direitos humanos dos apenados. Desta forma, o artigo em questão tem a finalidade de mostrar a importância da aplicação destes dispositivos no ordenamento jurídico do país, para que então seja possível obter um tratamento mais humanitário da populaçãocarcerária.

BACKGROUND Rilpivirine (RPV), a recently developed, once daily human immunodeficiency virus non-nucleoside reverse transcriptase inhibitor, is not currently approved for pediatric patients, but is sometimes prescribed for adolescents with multiple treatment failures, for regimen simplification or to minimize toxicity. Darunavir/ritonavir (DRV/r) administered once daily is also increasingly used in adolescents and may alter RPV pharmacokinetics (PK). We evaluated the PK interactions between RPV and DRV/r once daily in adolescents and young adults. METHODS Human immunodeficiency virus-infected subjects 12 to

To prevent mother-to-child-transmission of HIV-1, the 2010 WHO guidelines recommended prenatal zidovudine (ZDV) monotherapy (option A). To determine if ZDV monotherapy selects for HIV resistance in antiretroviral-naive women during pregnancy, specimens from 50 individuals were examined using pyrosequencing. ZDV-resistance mutations were detected at delivery in seven women (14%, 95% confidence interval 6.6-26.5%). These data raise the question whether women administered ZDV monotherapy for prevention of mother-to-child-transmission could have higher risk of virologic failure when later started on combination antiretroviral therapy, as has been demonstrated following single-dose nevirapine prophylaxis.

“La esencia de la teoría psicoanalítica es un discurso sin palabra”, afirma Lacan en la primera clase del seminario, libro 16, De un Otro al otro. ¿A qué nos puede remitir la paradoja de esta frase? En primer lugar, es posible llegar con Lacan a la tesis de que un significante no puede representarse a sí mismo, llevándonos, por tanto, al largo alcance de la expresión sí mismo para el propio significante. Habría, por así decir, una opacidad, una inconsistencia en la propia estructura significante, lo que nos obliga a concluir que no hay un punto de cierre del discurso, más aún, “no hay universo de discurso”. Traducimos tal afirmación clínicamente con la constatación de que siempre habrá lo que no se puede decir. Eso no significa tomar el discurso analítico como imposible, tampoco desvalorizarlo. Se trata de un impasse que es, sobre todo, lógico-matemático. El presente artículo, por tanto, presenta la radicalidad de la inconsistencia lógica del Otro como un correlato de un llamado a lo que Lacan denomina “espíritu del psicoanálisis” en un pronunciamiento que hace a su Escuela.

This study examined psychological functioning and beliefs about medicine in adolescents with human immunodeficiency virus (HIV) on highly active antiretroviral therapy in a community-based directly observed therapy (DOT) pilot feasibility study. Participants were youth with behaviorally acquired HIV (n = 20; 65% female; median age, 21 years) with adherence problems, who received once-daily DOT. Youth were assessed at baseline, week 12 (post-DOT), and week 24 (follow-up). At baseline, 55% of youth reported having clinical depressive symptoms compared to 27% at week 12 with sustained improvements at week 24. At baseline, substance use was reported within the borderline clinical range (T(score) = 68), with clinical but statistically nonsignificant improvement (T(score) = 61) at week 12. Hopelessness scores reflected optimism for the future. Coping strategies showed significantly decreased cognitive avoidance (p = .02), emotional discharge (p = .004), and acceptance/resignation ("nothing I can do," p = .004), whereas positive reappraisal and seeking support emerged. With the exception of depressive symptoms, week 12 improvements were not sustained at week 24. DOT adherence was predicted by higher baseline depression (p = .05), beliefs about medicine (p = .006) and perceived threat of illness scores (p = .03). Youth with behaviorally acquired HIV and adherence problems who participated in a community-based DOT intervention reported clinically improved depressive symptoms, and temporarily reduced substance use and negative coping strategies. Depressive symptoms, beliefs about medicine, and viewing HIV as a potential threat predicted better DOT adherence.

Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Funding Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).

Adherence to medications is critical to optimizing HIV care and is a major challenge in youth. The utility of directly observed therapy (DOT) to improve adherence in youth with HIV remains undefined and prompted this pilot study. Four U.S. sites were selected for this 24-week cooperative group study to assess feasibility and to identify the logistics of providing DOT to HIV-infected youth with demonstrated adherence problems. Once-a-day DOT was provided by DOT facilitators at the participant's choice of a community-based location and DOT tapered over 12 weeks to self-administered therapy based on ongoing adherence assessments. Twenty participants, median age 21 years and median CD4 227 cells/μl, were enrolled. Participants chose their homes for 82% of DOT visits. Compliance with recommended DOT visits was (median) 91%, 91%, and 83% at weeks 4, 8, and 12, respectively. Six participants completed >90% of the study-specified DOT visits and successfully progressed to self-administered therapy (DOT success); only half sustained >90% medication adherence 12 weeks after discontinuing DOT. Participants considered DOT successes were more likely to have higher baseline depression scores (p = 0.046). Via exit surveys participants reported that meeting with the facilitator was easy, DOT increased their motivation to take medications, they felt sad when DOT ended, and 100% would recommend DOT to a friend. In conclusion, this study shows that while community-based DOT is safe, feasible, and as per participant feedback, acceptable to youth, DOT is not for all and the benefits appear short-lived. Depressed youth appear to be one subgroup that would benefit from this intervention. Study findings should help inform the design of larger community-based DOT intervention studies in youth.

The goal of HAART is to promote reconstitution of CD4+ T cells and other immune responses. We evaluated the extent and the kinetics of immune reconstitution in HIV-infected children over 144 weeks of successful HAART.Thirty-seven children receiving their first HAART regimen had plasma HIV RNA; T cells and subpopulations; T-cell rearrangement excision circles (TREC) DNA; candida, HIVCD4 and HIVCD8 enzyme-linked immunospot measured at regular intervals.Plasma HIV RNA became undetectable in 81% of patients at 24 weeks and remained undetectable in 77% at 144 weeks. In contrast, CD4+% continuously increased. Distribution of T-cell subpopulations changed rapidly during the first 48 weeks of HAART and more slowly thereafter. At 144 weeks, total, naive and activated CD4+% and naive CD8+% of HIV-infected children were not significantly different from those of healthy age-matched controls, whereas total and activated CD8+% remained elevated. CD4 and CD8 TREC content increased only during the first 48 weeks of HAART. They positively correlated with each other and with total CD4+%, naive CD4+% and naive CD8+%. Candida and HIVCD4 enzyme-linked immunospot increased over time reaching peak values at 48 weeks and 144 weeks, respectively. HIVCD8 enzyme-linked immunospot decreased in magnitude over 144 weeks of HAART but retained its breadth. Baseline CD4+% positively correlated with CD4+% and with functional immune reconstitution at week 144, whereas baseline TREC correlated with TREC at week 144.HIV-infected children acquired normal distribution of CD4 T cells and other subpopulations and recovered CD4-mediated HIV immunity after 144 weeks of HAART.

BACKGROUND. Compliance with complex antiretroviral therapy regimens is a problem for HIV-1–infected children and their families. Simple, safe, and effective regimens are important for long-term therapeutic success. METHODS. A novel, once-daily dosing regimen of 3 antiretroviral drugs, emtricitabine, didanosine, and efavirenz, was tested in 37 therapy-naive HIV-infected children and adolescents between 3 and 21 years of age (inclusive). Subjects were followed for ≥96 weeks on an intention-to-treat basis. Signs, symptoms, plasma HIV-1 RNA viral load, CD4 counts, and safety laboratories were followed regularly. End points were the proportion of subjects with plasma HIV RESULTS. Thirty-seven subjects enrolled at 16 sites. Two subjects with rashes during the first 2 weeks of therapy were the only adverse events leading to study-drug discontinuation. Other early (before protocol-scheduled conclusion) study discontinuations included 3 viral failures on treatment and 5 patients who stopped therapy for apparently nonmedical reasons. Possible drug-related adverse events included 1 grade 4 low-glucose and 5 varied grade 3 events. There were no deaths. Virologic outcomes demonstrated that 32 (85%) of 37 subjects achieved viral suppression to CONCLUSIONS. A once-daily regimen of emtricitabine, didanosine, and efavirenz proved to be safe and tolerable and demonstrated good immunologic and virologic efficacy in this 2-year study.

Data on the combination of darunavir/ritonavir and etravirine both given twice daily in adolescents/young adults are lacking. In this study, we assessed the pharmacokinetics of darunavir/ritonavir 600/100 mg with etravirine 200 mg twice daily in 36 treatment-experienced human immunodeficiency virus-infected adolescents and young adults and found that exposures were comparable to those reported in adults.

Submitted by Boris Flegr (boris@uerj.br) on 2021-01-07T17:45:59Z No. of bitstreams: 1 Tese_Ana Paula Britto Rodrigues.pdf: 1690746 bytes, checksum: 3261f3834af7183104885e343ef44754 (MD5) Made available in DSpace on 2021-01-07T17:45:59Z (GMT). No. of bitstreams: 1 Tese_Ana Paula Britto Rodrigues.pdf: 1690746 bytes, checksum: 3261f3834af7183104885e343ef44754 (MD5) Previous issue date: 2015-11-24 Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro Esta investigación de tesis concentra sus intereses en la transmisión del psicoanálisis, más precisamente en su punto más radical que vienen deflagrar las huellas singulares de intransmisibilidad, punto congruente con la soledad del Uno-solo en su goce, término propuesto por Miller, en su lectura del axioma "Hay Uno" de Lacan, del campo uniano. En estos términos, la pregunta que rige la escritura de este trabajo se basa justamente en cerca de este "Hay Uno", más propiamente si su intransmisibilidad destinaría al psicoanálisis el rumbo de una práctica de un autismo a dos o un autismo entre varios. Se intenta así, también por medio de la expresión "hablar de sí", ubicar, reducir la soledad de ese Uno no solamente en una experiencia de análisis, una vez llevada hacia más lejos, como también en la redes sociales, por medio de un habla desinhibido y, en el campo de la literatura, por medio de la proliferación de las autobiografías y de algunas interesantes soluciones singulares Esta pesquisa de tese concentra seus interesses na transmissão da psicanálise, mais precisamente em seu ponto mais radical que vêm deflagrar as marcas singulares de intransmissibilidade, ponto congruente com a solidão do Um-sozinho em seu gozo, termo proposto por Miller, em sua leitura do axioma "Há Um" de Lacan, do campo uniano. Nesses termos, a pergunta que rege a escrita desse trabalho se assenta justamente em torno desse "Há Um", mais propriamente se sua intransmissibilidade destinaria à psicanálise o rumo de uma prática de um autismo a dois ou um autismo entre vários. Pretende-se assim, também por meio da expressão "falar de si", localizar, recortar a solidão desse Um não somente em uma experiência de análise, uma vez levada até mais longe, como também nas redes sociais, por meio de uma fala desinibida e, no campo da literatura, por meio da proliferação das autobiografias e de algumas interessantes soluções singulares

Few data are available regarding clinical outcomes or dosing requirements for the protease inhibitor ritonavir in human immunodeficiency virus (HIV)-infected children younger than under 24 months of age.This prospective, multicenter phase I/II open label treatment trial used ritonavir, zidovudine and lamivudine to treat protease inhibitor-naive, HIV-infected infants between the ages of 4 weeks and 24 months. Two sequential dosing cohorts were treated with 350 or 450 mg/m(2) ritonavir every 12 hours; this report includes results of pharmacokinetics, safety, tolerability and efficacy through 104 weeks of follow-up of all subjects.Fifty HIV-infected children were treated. By week 16, 36 had achieved HIV-1 RNA400 copies/mL (72% intent-to-treat, 84% as-treated analysis); by week 104, 18 maintained durable viral suppression (36% intent-to-treat, 46% as-treated). Poor medication adherence by caregiver report contributed to virologic failure. Few subjects experienced treatment-limiting toxicity: emesis or ritonavir refusal in 6 (12%); and severe but reversible anemia or elevated serum hepatic transaminases in 1 (4%) each. Apparent oral clearance was higher and the median predose concentrations were substantially lower than those found in adults. Median z scores for weight and height for age/gender were below normal at baseline but improved by week 104.A combination regimen of ritonavir, zidovudine and lamivudine was generally safe and produced sustained viral suppression in more than one-third of infants who initiated therapy before 2 years of age. Improved palatability of liquid preparations of protease inhibitors, supporting infrastructure and behavioral approaches to improve medication adherence with antiretrovirals will likely be necessary to further improve efficacy.

Depletion of CD4 T-cell counts or progression of human immunodeficiency virus (HIV) disease occurs rapidly in children, but few data address the efficacy of aggressive therapy for HIV-infected children.We evaluated the safety, tolerability, and activity of three regimens of antiretroviral therapy in a multicenter, open-label, phase 1-2 trial. Children infected with HIV type 1 (HIV-1) were stratified at entry according to age--three months or younger (early therapy) or older than three months (delayed therapy)--and assigned sequentially to one of three regimens. Children continued to receive treatment for up to 200 weeks if the plasma HIV-1 RNA level was less than 1000 copies per milliliter by 16 weeks.Plasma HIV-1 RNA levels fell from a median of 5.3 log copies per milliliter (range, 3.3 to 6.4 log copies per milliliter) at baseline to less than 1000 copies per milliliter at 16 weeks in 32 of 52 infants (62 percent). Plasma HIV-1 RNA levels were below 400 copies per milliliter at 48 weeks in 26 infants (50 percent) and at 200 weeks in 23 infants (44 percent). An intention-to-treat analysis revealed that significantly more children who received stavudine, lamivudine, nevirapine, and nelfinavir had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 48 weeks (83 percent) and 200 weeks (72 percent) than children who received reverse-transcriptase inhibitors alone (P=0.001 and P=0.01, respectively). Fewer infants in the delayed-therapy group than in the early-therapy group (30 percent vs. 60 percent) had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 200 weeks (P=0.03). Treatment-associated adverse effects were infrequent.In this phase 1-2 trial involving HIV-1-infected children, an age of three months or younger at the initiation of therapy and treatment with stavudine, lamivudine, nevirapine, and nelfinavir were associated with improved long-term viral suppression. Larger, randomized trials are required to define the optimal time to initiate therapy and the optimal regimen for these infants.

BACKGROUND Limited data are available for once-daily (QD) darunavir (DRV)/ritonavir (r) in the pediatric population. Coadministration of etravirine (ETR) may alter the pharmacokinetics (PK) of DRV. We evaluated the PK interactions between DRV/r (QD) and ETR QD or twice-daily (BID) in children, adolescents, and young adults. METHODS Human immunodeficiency virus-infected subjects 9 to < 24 years old on optimized background therapy including DRV/r 800/100 mg QD alone or combined with ETR 200 mg BID or ETR 400 mg QD were enrolled. Protocol-defined target drug exposure ranges based on adult data were used to assess the adequacy of each regimen. Intensive 24-hour blood sampling was performed, and PK parameters were determined using noncompartmental analysis. RESULTS Thirty-one subjects (14 males) completed the study; 16 received DRV/r QD alone (group 1), 6 received DRV/r plus ETR BID (group 2A), and 9 received DRV/r plus ETR QD (group 2B). The geometric mean (90% confidence interval [CI] geometric mean) for DRV area under the curve at 24 hours (AUC24) was 57.9 (49.6-67.6), 74.9 (44.4-126.5), and 66.4 (50.8-86.9) mg × h/L for patients in groups 1, 2A, and 2B, respectively. The increased DRV exposure when coadministered with ETR was not statistically significant. The geometric mean (90% CI geometric mean) of ETR AUC24 was 8.6 (4.4-16.8) and 11.9 (7.5-18.9) mg × h/L for groups 2A and 2B, respectively, with comparable C24. CONCLUSIONS The results suggest that DRV/r QD with ETR 400 mg QD or 200 mg BID is appropriate and support further evaluation of the safety and efficacy of the once-daily regimen in older children, adolescents, and young adults.

Objective: To identify modifiable obstetric factors associated with the failure of zidovudine chemoprophylaxis to prevent perinatal human immunodeficiency virus type 1 (HIV-1) transmission. Methods: We analyzed data from Pediatric AIDS Clinical Trials Group protocol 076, a randomized, double-masked, placebo-controlled trial that demonstrated that a zidovudine regimen could prevent perinatal HIV-1 transmission. We estimated the zidovudine treatment effect using the relative reduction in transmission risk among women randomized to treatment with zidovudine compared with women randomized to receive placebo. Univariate and multivariate statistical analyses were used to assess whether the treatment effect differed in magnitude according to potential antepartum or intrapartum risk factors. Results: In the univariate analysis, the zidovudine treatment effect was found to differ significantly in magnitude according to quartile of maternal weight at the time of study entry (interaction test, P = .03); among women in the heaviest-weight quartile (weight more than 82 kg), there was a 26% relative reduction in transmission risk, compared with a 79% relative reduction among the other three quartiles (interaction test, P = .05). In the zidovudine treatment group, women who transmitted HIV-1 were significantly more likely than nontransmitters to have had antepartum procedures or conditions associated with increased risk of fetal exposure to maternal blood or cervicovaginal secretions (43% compared with 19%, P = .04). In the multivariate analysis, adjustment for the plasma HIV-1 RNA level and CD4+ cell percentage did not eliminate the differential treatment effect according to these factors. Conclusion: High maternal weight and conditions associated with fetal exposure to maternal blood or cervicovaginal secretions may diminish the efficacy of zidovudine chemoprophylaxis.

Data on the combination of darunavir/ritonavir and etravirine both given twice daily in adolescents/young adults are lacking. In this study, we assessed the pharmacokinetics of darunavir/ritonavir 600/100 mg with etravirine 200 mg twice daily in 36 treatment-experienced human immunodeficiency virus-infected adolescents and young adults and found that exposures were comparable to those reported in adults.

"A essência da teoria psicanalítica é um discurso sem fala", afirma Lacan, na primeira aula do seminário, livro 16, De um Outro ao Outro. A que pode nos remeter o paradoxo desta frase? Já de saída, é possível extrairmos com Lacan a tese de que um significante não pode representar a si mesmo, levando-nos, portanto, ao longo alcance da expressão si mesmo, para o próprio significante. Haveria, por assim dizer, uma opacidade, uma inconsistência na própria estrutura significante, o que nos obriga a concluir que não há um ponto de fechamento do discurso, mais ainda, "não há universo de discurso". Traduzimos tal assertiva clinicamente com a constatação que sempre haverá o que não se pode dizer. Isso não significa tomar o discurso analítico como impossível, tampouco desvalorizá-lo. Trata-se de um impasse que é, sobretudo, lógico-matemático. O presente artigo, portanto, dedica-se em apresentar a radicalidade da inconsistência lógica do Outro como um correlato de uma convocação ao que Lacan chama de "espírito // "The essence of psychoanalytic theory is a discourse without words", Lacan says in the first class of the Seminar, book 16, From an Other to the other. Where can the paradox of this sentence send us to? First of all, according to Lacan, a signifier cannot represent itself. This takes us, therefore, to the long scope of the expression itself for the signifier proper. There would be, so to speak, an opacity, an inconsistency in the signifier structure itself, which leads us to conclude that there is no closing point of discourse, even more, "there is no universe of discourse". We clinically translate such statement verifying that there will always be what cannot be said. That does not mean taking the analytic discourse as impossible, nor devalue it. It is an impasse that is, above all, a logical-mathematical one. Hence this paper presents the radicality of the logical inconsistency of the Other as a correlate of a call to what Lacan names "spirit of psychoanalysis" when addressing his School.

HIV-infected children are treated with tenofovir in combination with other, potentially interacting, antiretroviral agents. We report the pharmacokinetic parameters of tenofovir in combination with efavirenz, darunavir-ritonavir, or atazanavir-ritonavir in HIV-infected children. HIV-infected patients 8 to 18 years of age receiving a tenofovir (300 mg)-based regimen containing efavirenz (300 or 600 mg) once daily (group 1), darunavir (300 or 600 mg)-ritonavir (100 mg) twice daily (group 2), or atazanavir (150 to 400 mg)-ritonavir (100 mg) once daily (group 3) were enrolled. Plasma samples were collected over a 24-h time interval. The 90% confidence intervals (90% CI) of the geometric means for the area under the plasma concentration-time curve (AUC) and the minimum concentration of drug in serum ( C min ) of each antiretroviral were computed and checked for overlap with intervals bracketing published values obtained in adult or pediatric studies demonstrating safety and/or efficacy. Group 1 efavirenz plasma concentrations were observed to be higher in patients receiving fixed-dose combination tablets compared with subjects receiving the individual formulation. In group 2, tenofovir and darunavir exposure was observed to be lower than expected. In group 3, tenofovir and atazanavir administered concomitantly produced exposures similar to those published for adult patients. The 90% CI of AUC and C min for tenofovir overlapped the target range for all combinations. Informal comparisons of treatment groups did not indicate any advantage to any combination with respect to tenofovir exposure. Further study of exposures achieved with antiretrovirals administered in combination is warranted.

An antiretroviral regimen containing efavirenz (EFV) plus lopinavir (LPV) boosted with ritonavir (RTV) in addition to nucleoside reverse transcriptase inhibitors (NRTI) is commonly administered throughout the world as second-line therapy for treatment of the human immunodeficiency virus because it has demonstrated efficacy in NRTI- and protease inhibitor-experienced adults.1 Although the EFV dose remains unchanged, LPV and RTV doses require adjustments when used in combination with EFV, because EFV induces their metabolism.2 Body weight adjusted doses are recommended for this combination in pediatric patients. However, controversy remains as to whether this approach is optimal because body surface area (BSA), which takes into account weight and height, is a better predictor of the physiological changes occurring with age.3 Thus, the objective of protocol P1058 conducted through the International Maternal Pediatric Adolescent AIDS Clinical Trials group was to examine the pharmacokinetics of interacting antiretroviral combinations, specifically EFV, LPV, and RTV, when dosed on a mg/m2 basis in HIV-infected children and adolescents.

Background: There are limited numbers of drugs that are available in formulations that are appropriate for neonates and few studies assessing resistance among infants born to human immunodeficiency virus (HIV)-infected women. Methods: Pharmacokinetics and tolerance of didanosine (ddl) were determined for infants ≤120 days of age. Infants received at least 24 hours of zidovudine (ZDV) treatment, followed by a single ddl dose and pharmacokinetic sampling. The target area under the concentration-time curve (AUC) was between 2.5 and 5.0 μM . hour. Toxicity and drug resistance mutations were assessed at baseline and follow-up times. Results: The initial ddl pharmacokinetic dosing of 50 mg/m 2 for infants >28 days of age achieved a median AUC 0- ∞ of 2.8 μM . hour. For infants ≤28 days of age, the target AUC was achieved after dose escalation from 25 mg/m 2 (median AUC 0- ∞, 1.4 μM . hour) to 50 mg/m 2 (median AUC 0- ∞, 5.40 μM . hour). At baseline, 25% of infected infants had drug resistance mutations (9 of 44 to ZDV and 2 of 44 to ddl). Resistance mutations were present for 29% of infants (5 of 17 infants) with in utero ZDV exposure and 25% (8 of 32 infants) with prior ZDV treatment. The most common ZDV mutation noted at baseline was the T215Y/F (n = 7) mutation; 2 of these infants also had the M41L mutation, which is associated with high level ZDV resistance. No prior exposure was noted for the 2 infants with ddI resistance, which indicates possible perinatal transmission of ddl-resistant virus to these infants. Conclusions: A dose of 50 mg/m 2 is the appropriate ddl dose for infants

Pediatric AIDS Clinical Trials Group protocol 316 was an international, multicenter, placebo-controlled trial comparing single-dose oral nevirapine (200 mg to mother and 2 mg/kg to infant) with placebo in human immunodeficiency virus (HIV)-infected pregnant women receiving standard antiretroviral therapy. This substudy evaluated the emergence of nevirapine-resistance mutations at 6 weeks postpartum in a subgroup of participants. Maternal risk factors for the emergence of nevirapine-resistance mutations were evaluated. Mutations associated with nevirapine resistance were detectable at delivery, prior to receipt of study drug, in 5 (2.3%) of 217 women. Fourteen (15%; 95% confidence interval, 8%-23%) of 95 women who received intrapartum nevirapine developed a nevirapine-resistance mutation 6 weeks postpartum. The most common mutation was K103N, which was present in 10 women. The risk for development of a new nevirapine-resistance mutation did not correlate with CD4 cell count or HIV-1 RNA load at delivery or with type of antepartum antiretroviral therapy. The risk of nevirapine resistance should be considered when determining the risks or benefits of intrapartum nevirapine in women receiving antepartum antiretroviral therapy.

Objective: To describe the effect of zidovudine on human immunodeficiency virus type 1 (HIV-1) and on the course of disease in infants who became infected while they and their mothers received zidovudine preventive therapy or placebo in Pediatric AIDS Clinical Trials Group Protocol 076. Study design: Observational substudy of a multicenter, randomized, double-blind, placebo-controlled trial. Methods: We compared the progression of disease, timing of HIV-1 transmission, and the plasma HIV-1 RNA level in infected infants of mother-infant pairs who were randomly assigned to receive zidovudine (n = 14) or placebo (n = 43). The development of genotypic zidovudine resistance was assessed among infected infants in the zidovudine treatment group. Results: In this limited study, zidovudine therapy during pregnancy and labor and in the neonatal period for 6 weeks failed to have a major effect on rapid progression of disease, timing of transmission, and viral replication in HIV-infected infants. When the zidovudine treatment regimen failed to prevent maternal-infant transmission of HIV-1, resistance to zidovudine did not develop during study treatment. Conclusions: Our study supports the safety of zidovudine use in pregnancy and in the newborn period but demonstrates the continued need for more potent antiretroviral treatment of the infected infant. (J Pediatr 1999;134:717-24)

The objective was to determine the safety of the zidovudine (ZDV) regimen utilized in the Pediatric AIDS Clinical Trial Group (ACTG) 076 study. ACTG 076 was a randomized double-blind placebo-controlled trial which demonstrated that a ZDV regimen could prevent mother-to-child HIV-1 transmission. Infants were followed through 18 months of age and women were followed through 6 months postpartum. Maternal complications pregnancy outcomes growth and development of the uninfected infants and HIV-1 disease progression in the women were monitored prospectively. Maternal therapy was well tolerated. There was no serious pattern of adverse pregnancy outcomes associated with ZDV use. Amongst the ZDV-exposed infants the only recognized toxicity was anemia within the first 6 weeks of life; the risk for anemia was not associated with premature delivery duration of maternal treatment degree of maternal immunosuppression or maternal anemia. ZDV treatment was not associated with an increased incidence of newborn structural abnormalities. At 18 months of age uninfected infants did not differ in growth parameters or immune function. No childhood neoplasias were reported in either group. In the women at 6 months postpartum there were no differences in clinical immunologic or virologic disease progression. There were no identified problems that would alter current recommendations for the routine use of ZDV for the prevention of mother--child HIV-1 transmission. (authors)

Maternal samples were assessed from 96 women enrolled in Pediatric AIDS Clinical Trials Group protocol 076 to determine the prevalence of human immunodeficiency virus type 1 (HIV-1) genotypic zidovudine resistance at entry, if zidovudine resistance developed on study, and the role of zidovudine resistance in vertical transmission of HIV-1 despite zidovudine therapy. Low and high levels of genotypic resistance were assessed by differential hybridization, oligoligation, or direct sequencing of plasma HIV-1 RNA for codons K70R and T215Y/F. None of the women had high-level genotypic resistance to zidovudine at study entry or delivery. For low-level zidovudine resistance, the 95% confidence intervals were 0.3%-6.8% for baseline prevalence and 0.3%-14% for delivery incidence. Low-level zidovudine resistance, adjusted for plasma viral RNA level at delivery, was not strongly associated with an increase in vertical transmission risk (odds ratio, 4.8; 95% confidence interval, 0.2-131; P = .35).

ContextA 2-dose intrapartum/newborn nevirapine regimen reduced perinatal human immunodeficiency virus (HIV) transmission in Ugandan women not receiving antenatal antiretroviral therapy (ART). However, it is unknown whether the addition of the 2-dose nevirapine regimen to standard ART would further reduce perinatal HIV transmission.ObjectiveTo determine whether a 2-dose nevirapine regimen can decrease perinatal transmission of HIV in nonbreastfeeding women receiving standard ART.Design and SettingInternational, blinded, placebo-controlled, phase 3 trial enrolling women between May 1997 and June 2000 at clinical sites providing care for HIV infection throughout the United States, Europe, Brazil, and the Bahamas.ParticipantsA total of 1270 women received nevirapine (n = 642) or placebo (n = 628). Infants were followed up for 6 months to determine HIV-infection status, which was available for 1248 deliveries.InterventionA 200-mg dose of oral nevirapine to women after onset of labor and a 2-mg/kg dose of oral nevirapine to newborns between 48 and 72 hours after birth.Main Outcome MeasuresDetection of HIV infection in infants and grade 3 and 4 toxic effects in women and newborns.ResultsAfter review by the data and safety monitoring board, the trial was stopped early because the overall transmission rates were significantly lower than assumed for the study design. Antenatal ART included zidovudine alone in 23%; combinations without protease inhibitors in 36%; and combinations with protease inhibitors in 41%. Thirty-four percent of women had elective cesarean delivery. No significant safety concerns were identified for women or infants. Detection of HIV infection occurred in 9 (1.4%; 95% confidence interval [CI], 0.6%-2.7%) of 631 nevirapine group deliveries and 10 (1.6%; 95% CI, 0.8%-2.9%) of 617 placebo group deliveries. The 95% CI for the difference in transmission rate (−0.2) between the 2 study arms ranged from −1.5% in favor of nevirapine to 1.2% in favor of placebo (P = .82, Fisher exact test). The transmission rate was higher in women with lower baseline CD4 cell counts and higher delivery HIV RNA levels, but there was no significant difference between treatment arms in any subgroup.ConclusionRisk of perinatal HIV transmission was low and no benefit from additional intrapartum/newborn nevirapine was demonstrated when women received prenatal care and antenatal ART, and elective cesarean section was made available.

Nelfinavir dosed at approximately 20 to 30 mg/kg three times a day (TID) in older children provides exposure similar to 750 mg TID in adults. However, the pharmacokinetics (PK) of nelfinavir in infants who are2 years of age is not well-described. The objective of this study was to determine the pharmacokinetics of nelfinavir in infants2 years of age.Nelfinavir concentrations were evaluated in 22 HIV-infected infants between 15 days and 2 years of age receiving nelfinavir as part of Pediatric ACTG Study 356. Nelfinavir therapy was initiated at approximately 25 mg/kg TID (n = 18) or approximately 55 mg/kg twice a day (n = 4) and given in combination with nevirapine, stavudine and lamivudine. PK samples were obtained predose and 1.5 and 4 h postdose at approximately 6-month intervals. Eight infants (allor = 3 months of age) also had intensive PK samples collected at Week 1.The median apparent clearance in the infants with intensive pharmacokinetic sampling was 2.7 liters/h/kg (range, 1.8 toor = 10) and was similar between twice a day and TID dosing cohorts. Overall nelfinavir concentrations at all collection times were lower in these infants than previously reported in older pediatric patients.Nelfinavir concentrations in infants are highly variable and lower than those seen in adult or older pediatric populations receiving labeled dosing. Therefore it is necessary to further evaluate nelfinavir safety, effectiveness and pharmacokinetics at higher doses than used among other pediatric populations.

A double-blind phase II trial compared zalcitabine (0.03 mg/kg/day) in combination with zidovudine (720 mg/m2/day) and zidovudine monotherapy in 250 clinically stable, previously zidovudine-treated, human immunodeficiency virus-infected children. The combination was well-tolerated except for an increased incidence of neutropenia (14%) compared with that in children receiving monotherapy (5%). No differences were noted for time to first AIDS-defining illness or death, neuropsychologic status, or weight Z scores. In patients in the combination arm, the CD4 cell count decline was slower (13% per year) than in patients receiving monotherapy (25% per year) (P = .03), and quantitative peripheral blood mononuclear cell virus load remained lower at all time points (P = .08). Deaths were fewer in patients receiving combination therapy (4) compared with those in patients receiving monotherapy (10) (P = .083). Thus, administration of zidovudine with zalcitabine to children with prior zidovudine treatment did not result in a significant increase in toxicity compared with that resulting from zidovudine monotherapy and demonstrated improvement in immunologic and virologic surrogate markers.