Análise morfológica e fisiológica dos fígados e rins de ratas prenhes e seus fetos tratados pela associação zidovudina, lamivudina e ritonavir durante toda a prenhez

OBJETIVO: avaliar os efeitos da administração da associação zidovudina-lamivudina-ritonavir nos fígados e rins de ratas prenhes e seus conceptos do ponto de vista morfológico e fisiológico. MÉTODOS: 40 ratas albinas prenhes foram aleatoriamente divididas em 4 grupos: 1 controle (Ctrl: controle de veículo) e 3 experimentais (Exp1x, Exp3x e Exp9x). Estes últimos foram tratados por solução oral de zidovudina/lamivudina/ritonavir (Exp1x: 10/5/20 mg/kg; Exp3x: 30/15/60 mg/kg; Exp9x: 90/45/180 mg/kg). As drogas e o veículo foram administrados por gavagem, desde o 1º até o 20º dia de prenhez. No último dia do experimento, todos os animais foram anestesiados e sangue foi retirado da cavidade cardíaca para avaliação sérica das enzimas aspartato aminotransferase (AST) e alanina aminotransferase (ALT), por método calorimétrico, bem como da ureia, determinada por método cinético-enzimático, e creatinina, por método cinético-colorimétrico. Em seguida, fragmentos dos fígados e rins maternos e fetais foram coletados, fixados em formol a 10% e processados segundo os métodos histológicos para inclusão em parafina. Cortes com 5 µm de espessura foram corados pela hematoxilina-eosina (HE) e analisados por microscopia de luz. Na leitura das lâminas, considerou-se o padrão de normalidade para fígado e rins, tais como: hepatócitos, espaço porta íntegros e veias hepáticas bem definidas. Nos rins, a presença de corpúsculos renais, túbulos contorcidos e alças de Henle típicos. Nos fígados fetais considerou-se, ainda, a morfologia das células da linhagem eritrocitária nas diferentes fases do desenvolvimento, bem como os megacariócitos. Quando houve alteração da coloração padrão estabelecida para as estruturas hepáticas e renais, alteração na morfologia de núcleos, rompimento de limites de alguma organela citoplasmática, presença de congestão vascular, tudo isso foi entendido como provavelmente provocado pelas drogas em sua(s) dose(s) de aplicação. A avaliação estatística foi realizada por análise de variância (ANOVA), completada pelo teste de Tukey-Kramer (p<0,05). RESULTADOS: os fígados maternos dos grupos Ctrl, Exp1x e Exp3x mostraram hepatócitos típicos, espaço porta íntegros e veias hepáticas com aspecto normal. No fígado materno do grupo Exp9x, foram encontrados hepatócitos com sinais de atrofia e apoptose (eosinofilia citoplasmática e núcleos picnóticos). Além disso, identificou-se vasodilatação dos capilares sinusoides (congestão). Os rins maternos dos grupos Ctrl e Exp1x apresentaram-se normais, com corpúsculos renais, túbulos contorcidos e alças de Henle típicos. Já nos grupos Exp3x e Exp9x, foram encontrados congestão vascular, glomérulos pequenos ricos em células contendo núcleos hipercromáticos, sendo mais intensos no Exp9x. Com relação aos fígados e rins fetais, não foram observadas alterações morfológicas ou fisiológicas nos grupos estudados. Encontrou-se aumento significante nos níveis da AST (305,70±55,80; p<0,05) e da creatinina (0,50±0,09; p<0,05) no grupo Exp9x. CONCLUSÕES: nossos resultados evidenciam que a administração da associação zidovudina/lamivudina/ritonavir a ratas prenhes em altas doses causa alterações morfológicas e funcionais nos fígados e rins maternos. Não houve alterações nem morfológicas nem fisiológicas nos fígados e rins fetais.

Antiretroviral resistance among HIV type 1-infected women first exposed to antiretrovirals during pregnancy: Plasma versus PBMCs

Resistance-associated mutations (RAMs) in plasma samples from HIV-1-infected women who received antiretroviral (ARV) prophylaxis during pregnancy was assessed and correlated with the detection of RAMs in peripheral blood mononuclear cells (PMBCs). The study population was composed of HIV-1-infected women enrolled in a prospective cohort study in Latin America and the Caribbean (NISDI Perinatal Study) as of March 1, 2005, who were diagnosed with HIV-1 infection during the current pregnancy, who received ARVs during pregnancy for prevention of mother-to-child transmission of HIV-1, and who were followed through at least the 6-12 week postpartum visit. Plasma samples collected at enrollment during pregnancy and at 6-12 weeks postpartum were assayed for RAMs. Plasma results were compared to previously described PBMC results from the same study population. Of 819 enrolled subjects, 197 met the eligibility criteria. Nucleic acid amplification was accomplished in 123 plasma samples at enrollment or 6-12 weeks postpartum, and RAMs were detected in 22 (17.9%; 95% CI: 11.7-25.9%). Previous analyses had demonstrated detection of RAMs in PBMCs in 19 (16.1%). There was high concordance between RAMs detected in plasma and PBMC samples, with only eight discordant pairs. The prevalence of RAMs among these pregnant, HIV-1-infected women is high (>15%). Rates of detection of RAMs in plasma and PBMC samples were similar.

Evaluation of IGF-2/ApaI polymorphism in pregnant women infected with human immunodeficiency virus type 1 taking antiretroviral drugs

Objective: Studies carried Out to assess the effects of antiretroviral drugs (ARV) in HIV-1 infected pregnant women have demonstrated carbohydrate intolerance. Some reports also refer to the effect of disturbances in the expression of the insulin-like growth factor (IGF) system on pancreas beta-cell function in humans and IGF-2/ApaI polymorphisms have been associated with obesity and features of the metabolic syndromes. in the present study, we tested the association between IGF-2/ApaI genotype and hyperglycemia in HIV-1 infected pregnant women receiving ARV. Design: We studied IGF-2/ApaI polymorphism in 87 healthy pregnant women, 43 HIV-1 infected pregnant women taking ARV with hyperglycemia during pregnancy, and 43 HIV-1-negative pregnant women with gestational diabetes. Blood samples were obtained for DNA extraction, PCR and genotyping. Data were analyzed statistically by the Kolmogorov-Smirnov normality, ANOVA and chi-square tests. Results: There were no significant differences in genotype frequency among the three groups analyzed. Considering the HIV-1-infected pregnant women, there were no significant differences in genotype frequency between the zidovudine group and the triple antiretroviral treatment group. There were no significant differences in allele frequencies among the groups evaluated. Non-white pregnant women tended to present the GG genotypes compared to white pregnant women. Conclusion: These results contribute to a better understanding of metabolic glycemic disorders in HIV-1 infected pregnant women using ARV, showing that IGF-2/ApaI polymorphisms are not responsible as a single Causative factor of glycemic alterations. These data indicate that other variables should be studied in order to explain these glycemic abnormalities. (C) 2009 Elsevier Ltd. All rights reserved.

IL23R polymorphisms influence phenotype and response to therapy in patients with ulcerative colitis

Objective - We aimed to identify the clinical and genetic [IL23 receptor (IL23R) single nucleotide polymorphisms (SNPs)] predictors of response to therapy in patients with ulcerative colitis. Patients and methods - A total of 174 patients with ulcerative colitis, 99 women and 75 men, were included. The mean age of the patients was 47±15 years and the mean disease duration was 11±9 years. The number of patients classified as responders (R) or nonresponders (NR) to several therapies was as follows: 110 R and 53 NR to mesalazine (5-ASA), 28 R and 20 NR to azathioprine (AZT), 18 R and 7 NR to infliximab. Clinical and demographic variables were recorded. A total of four SNPs were studied: IL23R G1142A, C2370A, G43045A, and G9T. Genotyping was performed by real-time PCR using Taqman probes. Results - Older patients were more prone to respond to 5-ASA (P=0.004), whereas those with pancolitis were less likely to respond to such therapies (P=0.002). Patients with extraintestinal manifestations (EIMs) were less likely to respond to 5-ASA (P=0.001), AZT (P=0.03), and corticosteroids (P=0.06). Carriers of the mutant allele for IL23R SNPs had a significantly higher probability of developing EIMs (P<0.05), a higher probability of being refractory to 5-ASA (P<0.03), but a higher likelihood of responding to AZT (P=0.05). A significant synergism was observed between IL23R C2370A and EIMs with respect to nonresponse to 5-ASA (P=0.03). Conclusion - Besides extent of disease and age at disease onset, the presence of EIMs may be a marker of refractoriness to 5-ASA, corticosteroids, and AZT. IL23R SNPs are associated both with EIMs and with nonresponse to 5-ASA and corticosteroids.

HIV rapid testing as a key strategy for prevention of mother-to-child transmission in Brazil

OBJECTIVE: To assess the feasibility of HIV rapid testing for pregnant women at maternity hospital admission and of subsequent interventions to reduce perinatal HIV transmission. METHODS: Study based on a convenience sample of women unaware of their HIV serostatus when they were admitted to delivery in public maternity hospitals in Rio de Janeiro and Porto Alegre, Brazil, between March 2000 and April 2002. Women were counseled and tested using the Determine HIV1/2 Rapid Test. HIV infection was confirmed using the Brazilian algorithm for HIV infection diagnosis. In utero transmission of HIV was determined using HIV-DNA-PCR. There were performed descriptive analyses of sociodemographic data, number of previous pregnancies and abortions, number of prenatal care visits, timing of HIV testing, HIV rapid test result, neonatal and mother-to-child transmission interventions, by city studied. RESULTS: HIV prevalence in women was 6.5% (N=1,439) in Porto Alegre and 1.3% (N=3.778) in Rio de Janeiro. In Porto Alegre most of women were tested during labor (88.7%), while in Rio de Janeiro most were tested in the postpartum (67.5%). One hundred and forty-four infants were born to 143 HIV-infected women. All newborns but one in each city received at least prophylaxis with oral zidovudine. It was possible to completely avoid newborn exposure to breast milk in 96.8% and 51.1% of the cases in Porto Alegre and Rio de Janeiro, respectively. Injectable intravenous zidovudine was administered during labor to 68.8% and 27.7% newborns in Porto Alegre and Rio de Janeiro, respectively. Among those from whom blood samples were collected within 48 hours of birth, in utero transmission of HIV was confirmed in 4 cases in Rio de Janeiro (4/47) and 6 cases in Porto Alegre (6/79). CONCLUSIONS: The strategy proved feasible in maternity hospitals in Rio de Janeiro and Porto Alegre. Efforts must be taken to maximize HIV testing during labor. There is a need of strong social support to provide this population access to health care services after hospital discharge.

Pulmonary thromboembolism in AIDS patient with chronic venous insufficiency, pulmonary tuberculosis and breast cancer: a case report and pathophysiology review

Recent literature reports thrombotic episodes occurring in patients with HIV infection associated with other abnormalities including neoplasms and infections predisposing to a hypercoagulable state. We report a 47-year-old woman who developed pulmonary thromboembolism in association with HIV infection, pulmonary tuberculosis and breast cancer. She was treated with rifampin, isoniazid, pyrazinamide; heparin, phenprocoumon, zidovudine, lamivudine and efavirenz. Acid fast bacilli were visualized in a sputum smear and three months after, Mycobacterium tuberculosis was isolated from lymph node biopsy during a episode of immune reconstitution. The isolated mycobacteria showed sensitivity to all first-line drugs. HIV infection, breast cancer and pulmonary tuberculosis have several mechanisms that induce hypercoagulable state and can lead to thromboembolic complications. Pulmonary thromboembolism in this patient was a diagnostic challenge because of all the other severe diseases that she experienced at the same time.

Rapid HIV diagnostic test in undocumented pregnant women applied at an inner-city teaching hospital

A significant number of Brazilian gestational-age women are still not tested for HIV, representing a high risk of transmission to their newborns. The current study sought to identify the number of pregnant women with no previous testing or undocumented for HIV referred to the Gynecology and Obstetrics Department of a Regional Teaching Hospital and included diagnosis of HIV infection determined by a rapid test and perinatal transmission in pregnancy. Medical records of all pregnant women admitted to hospital from January 2001 to December 2005 were reviewed. Pregnant women without HIV results were submitted to a rapid HIV test. Those who tested positive were further tested by ELISA and confirmed by indirect immunofluorescence assay (IIA) or Western blot (WB). The viral load from babies born to HIV-infected mothers was assessed by bDNA. Of the 16,424 pregnant women analyzed (6.6%), 1,089 were undocumented for HIV. Eleven women were positive in rapid testing and 10 were confirmed by ELISA, IIA or WB, with 0.9% seropositivity. Mother/infant pairs received zidovudine monotherapy prophylaxis and infant viral load was lower than 50 copies/mL. A higher number of pregnant women previously tested for HIV during antenatal care was verified, compared to that obtained nationwide.

HIV-1-mother-to-child transmission and associated characteristics in a public maternity unit in Presidente Prudente, Brazil

In children, vertical transmission is the main form of HIV infection. Our aim was to determine the prevalence of HIV-1 vertical transmission in mother-infant pairs in a public maternity ward in Presidente Prudente, SP. Additionally; we sought to identify characteristics associated with this form of transmission. The files of 86 HIV-1-infected mothers and their newborns referred to a Public Hospital from March 2002 to March 2007 were analyzed. The HIV-1-RNA viral load of the newborns was determined by bDNA. The HIV-1 vertical-transmission rate was 4.6%. Children that were born in the pre-term period and breastfed were at a higher risk of HIV-1 infection (p = 0.005 and p = 0.017 respectively) than children born at term and not breastfed. Prophylactic therapy with zidovudine after birth for newborns was associated with a lower risk of infection (p = 0.003). The number of newborns weighing < 2,500 g was significantly higher for infected children (p = 0.008) than for non-infected newborns. About 22.9% of mothers did not know the HIV-1 status of their newborns eight months after delivery. The study suggests that it is necessary to increase the identification of HIV-1 infection in pregnant women and their newborns as well as to offer and explain the benefits of ARV prophylaxis.

VIH: Interferência na Isoimunização RhD?

Introdução: A isomunização RhD continua a existir continuando a sua gravidade a ser imprevisível. Material e métodos: Descreve-se um caso clínico duma grávida com dupla seropositividade para o VIH 1 e 2, que, após uma gravidez com uma isoimunização RhD grave teve duas gravidezes sem que esta se tenha manifestado com a mesma gravidade. Realizou-se ensaio in vitro para se testar a hipótese de a terapêutica anti-retrovírica com zidovudina (AZT) interferir no reconhecimento dos antigénios eritrocitários. Resultados: O AZT, in vitro, não alterou o reconhecimento eritrocitário do antigénio D, responsável pelo fenótipo RhD. Discussão: Discute-se a vigilância ecográfica da gravidade da anemia fetal e as hipóteses implicadas na alteração de comportamento da isoimunização RhD. Conclusão: Na avaliação da descompensação da anemia fetal existem marcadores ecográficos preditivos da anemia fetal como a velocidade do pico sistólico na artéria cerebral média que devem ser integrados numa avaliação do bem-estar fetal, antes da realização da amniocentese. Ainda permanece por elucidar a razão da diversidade do comportamento da imunização RhD, como no caso clínico descrito.

USE OF LOPINAVIR/RITONAVIR ASSOCIATED WITH ERGOTAMINE RESULTING IN FOOT AMPUTATION: BRIEF COMMUNICATION

A 32-year-old female, was diagnosed in 2004 with a C1 HIV1 infection, using zidovudine/lamivudine 300/150 mg BID and lopinavir/ritonavir 400/100 mg BID, in addition to prophylaxis with trimethoprim-sulfamethoxazole 800/160 mg QD, but no prophylaxis with macrolide antibiotics. The patient presented with a severe headache and was prescribed two capsules of the anti-migraine drug Ormigrein™, which contained ergotamine tartrate 1 mg, caffeine 100 mg, paracetamol 220 mg, hyoscyamine sulfate 87.5 mcg, and atropine sulfate 12.5 mcg. Afterwards she was prescribed one capsule of Ormigrein every 30 minutes for a total of six capsules a day. The patient took the medication as prescribed but developed a pain in her left ankle three days later, which evolved to the need for amputation.

Impacto do tratamento antirretroviral na ocorrência de macrocitose em pacientes com HIV/AIDS do município de Maringá, Estado do Paraná

INTRODUÇÃO: AIDS é uma doença causada pelo HIV que compromete o sistema imune do organismo. O advento da terapia antirretroviral (TARV) altamente eficaz promoveu melhora substancial do prognóstico da doença e da qualidade de vida dos pacientes com HIV/AIDS. Durante seu tratamento prolongado, notam-se algumas alterações hematológicas, dentre elas, anemia e macrocitose, bem como carências de micronutrientes, tais como, de vitamina B12 e ácido fólico. O objetivo do presente trabalho é relacionar a macrocitose e anemia ao uso de TARV, ou à deficiência de vitamina B12 ou de ácido fólico. MÉTODOS: Foram avaliados 110 pacientes HIV positivos, comparando-se aqueles em uso de TARV com zidovudina (AZT) (grupo 1), TARV sem AZT (grupo 2) ou sem uso de TARV (grupo 3). RESULTADOS: Os pacientes dos três grupos não apresentaram diferenças estatísticas significativas quanto aos níveis de hemoglobina (p = 0,584) e de ácido fólico (p = 0,956). Os pacientes do grupo 1 (G1) apresentaram volume corpuscular médio (VCM) aumentado quando comparado ao grupo 3 (G3) (p < 0,05), bem como do grupo 2 (G2) em relação ao G3 (p < 0,001). As dosagens de vitamina B12 do G1 e G3 foram menores do que as encontradas pelo G2 (p = 0,008). CONCLUSÕES: Conclui-se que os indivíduos em uso de TARV apresentaram macrocitose, embora não pudesse ser relacionada ao tipo de TARV ou a deficiência de vitamina B12. Entretanto, a deficiência de ácido fólico não esteve relacionada ao uso de TARV e nem à macrocitose.

Evaluation of inadequate anti-retroviral treatment in patients with HIV/AIDS

INTRODUCTION: Since the emergence of antiretroviral therapy, the survival of patients infected with human immunodeficiency virus has increased. Non-adherence to this therapy is directly related to treatment failure, which allows the emergence of resistant viral strains. METHODS: A retrospective descriptive study of the antiretroviral dispensing records of 229 patients from the Center for Health Care, University Hospital, Federal University of Juiz de Fora, Brazil, was conducted between January and December 2009. RESULTS: The study aimed to evaluate patient compliance and determine if there was an association between non-adherence and the therapy. Among these patients, 63.8% were men with an average age of 44.0 ± 9.9 years. The most used treatment was a combination of 2 nucleoside reverse transcriptase inhibitors with 1 non-nucleoside reverse transcriptase inhibitor (55.5%) or with 2 protease inhibitors (28.8%). It was found that patients taking lopinavir/ritonavir with zidovudine and lamivudine had a greater frequency of inadequate treatment than those taking atazanavir with zidovudine and lamivudine (85% and 83.3%, respectively). Moreover, when the combination of zidovudine/ lamivudine was used, the patients were less compliant (χ2 = 4.468, 1 degree of freedom, p = 0.035). CONCLUSIONS: The majority of patients failed to correctly adhere to their treatment; therefore, it is necessary to implement strategies that lead to improved compliance, thus ensuring therapeutic efficacy and increased patient survival.

Evaluation of preventive measures for mother-to-child transmission of HIV in Aracaju, State of Sergipe, Brazil

INTRODUCTION: The main route of human immunodeficiency virus (HIV) infection in children is from mother to child. The preventive measures established for the Aids Clinical Trial Group protocol 076 (ACTG 076) significantly reduces HIV vertical transmission rates. This study aims to evaluate the implementation of the ACTG 076 protocol in the maternity units of State of Sergipe, Brazilian northeast. METHODS: This is a descriptive, retrospective study with a quantitative approach, with HIV positive women and children exposed, attending a Maternity reference for high-risk pregnancies. Data were obtained from patient records registered in the years 1994 to 2010. RESULTS: Amongst the 110 pregnant women and exposed newborns, the ACTG 076 protocol was fully utilized in only 31.8% of the participants. During the prenatal period, zidovudine (ZDV) was taken by 79.1% of the pregnant women. Only 49.1% of HIV seropositive patients used ZDV during delivery. Two (1.8%) children were considered infected and 50 (45.5%) do not have a conclusive diagnosis to date. CONCLUSIONS: There were significant deficiencies in the prevention of mother-to-child transmission of HIV, including lack of compliance with the three phases of the ACTG 076 protocol; inadequacies in prenatal care; inappropriate mode of delivery and lack of adequate follow up of exposed children.

Study of the cardiac alterations in HIV-infected children consequent to the antiretroviral therapy: prospective study of 47 cases

OBJECTIVE: Detect of cardiac alterations in children with AIDS and compare their evolution with the administration of only one anti-retroviral and the recent cases who received drugs in combination. METHODS: We prospectively studied 47 children in 3 groups: group 1, 20 cases treated only with zidovudine; group 2, 10 patients treated initially with zidovudine and later with a combination of drugs and in group 3, 17 patients, who receiced two or three since the beginning. In all patients it was done chest X-ray, EKG and echocardiography every 6 months and after death complete pathological study. RESULTS: Among the 45 patients cases 26 (57%) were index cases. Malnutrition, diarrhea tachycardia, signs of congestive heart failure, pericardial effusion, abnormal ventricular repolarization and arrhythmias were more frequent in group 1. Echocardiographic abnormalities were present in 10 (50%) children of group 1. They were less frequent in the others two groups. In regard to the outcome in group 1, two patients had worsening of sings of cardiomyopaty and 4 died. Cardiac dysfunction in all cases of group 2 and 3 improved with the medication. CONCLUSION:- The children who received combination and their cardiac alterations had more favorable outcome than those who received only one drug.

Estudio de nuevos compuestos con potencial actividad biológica

El presente plan de trabajo es la continuación de un proyecto de investigación apoyado en períodos anteriores y está orientado hacia la síntesis, estudios preclínicos y de preformulación de derivados de compuestos de probada actividad biológica: 1) Naftoquinonas halogenadas y 2) 3'-azido-3'-deoxitrimidina (AZT). Objetivos Generales: Se realizarán variaciones estructurales sobre compuestos "líder" de probada actividad biológica como las Naftoquinonas halogenadas y la 3'-azido-3'-deoxitrimidina (AZT). Objetivos Específicos: La búsqueda de nuevas alternativas terapéuticas con mayor actividad biológica y menor toxicidad que sus precursores, nos condujo al desarrollo, al estudio de estabilidad y de algunas propiedades físico-químicas y a la evaluación de la actividad biológica de potenciales fármacos.