Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study.

BACKGROUND: Poor tolerance and adverse drug reactions are main reasons for discontinuation of antiretroviral therapy (ART). Identifying predictors of ART discontinuation is a priority in HIV care. METHODS: A genetic association study in an observational cohort to evaluate the association of pharmacogenetic markers with time to treatment discontinuation during the first year of ART. Analysis included 577 treatment-naive individuals initiating tenofovir (n = 500) or abacavir (n = 77), with efavirenz (n = 272), lopinavir/ritonavir (n = 184), or atazanavir/ritonavir (n = 121). Genotyping included 23 genetic markers in 15 genes associated with toxicity or pharmacokinetics of the study medication. Rates of ART discontinuation between groups with and without genetic risk markers were assessed by survival analysis using Cox regression models. RESULTS: During the first year of ART, 190 individuals (33%) stopped 1 or more drugs. For efavirenz and atazanavir, individuals with genetic risk markers experienced higher discontinuation rates than individuals without (71.15% vs 28.10%, and 62.5% vs 14.6%, respectively). The efavirenz discontinuation hazard ratio (HR) was 3.14 (95% confidence interval (CI): 1.35-7.33, P = .008). The atazanavir discontinuation HR was 9.13 (95% CI: 3.38-24.69, P < .0001). CONCLUSIONS: Several pharmacogenetic markers identify individuals at risk for early treatment discontinuation. These markers should be considered for validation in the clinical setting.

Anti-HSV-1 and anti-HIV-1 activity of gallic acid and pentyl gallate

The synthetic n-alkyl esters of gallic acid (GA), also known as gallates, especially propyl, octyl and dodecyl gallates, are widely employed as antioxidants by food and pharmaceutical industries. The inhibitory effects of GA and 15 gallates on Herpes Simplex Virus type 1 (HSV-1) and Human Immunodeficiency Virus (HIV-1) replication were investigated here. After a preliminary screening of these compounds, GA and pentyl gallate (PG) seemed to be the most active compounds against HSV-1 replication and their mode of action was characterized through a set of assays, which attempted to localize the step of the viral multiplication cycle where impairment occurred. The detected anti-HSV-1 activity was mediated by the inhibition of virus attachment to and penetration into cells, and by virucidal properties. Furthermore, an anti-HIV-1 activity was also found, to different degrees. In summary, our results suggest that both compounds could be regarded as promising candidates for the development of topical anti-HSV-1 agents, and further studies concerning the anti-HIV-1 activity of this group of molecules are merited.

Inhibition of the integrase of human immunodeficiency virus (HIV) type 1 by anti-HIV plant proteins MAP30 and GAP31.

MAP30 (Momordica anti-HIV protein of 30 kDa) and GAP31 (Gelonium anti-HIV protein of 31 kDa) are anti-HIV plant proteins that we have identified, purified, and cloned from the medicinal plants Momordica charantia and Gelonium multiflorum. These antiviral agents are capable of inhibiting infection of HIV type 1 (HIV-1) in T lymphocytes and monocytes as well as replication of the virus in already-infected cells. They are not toxic to normal uninfected cells because they are unable to enter healthy cells. MAP30 and GAP31 also possess an N-glycosidase activity on 28S ribosomal RNA and a topological activity on plasmid and viral DNAs including HIV-1 long terminal repeats (LTRs). LTRs are essential sites for integration of viral DNA into the host genome by viral integrase. We therefore investigated the effect of MAP30 and GAP31 on HIV-1 integrase. We report that both of these antiviral agents exhibit dose-dependent inhibition of HIV-1 integrase. Inhibition was observed in all of the three specific reactions catalyzed by the integrase, namely, 3' processing (specific cleavage of the dinucleotide GT from the viral substrate), strand transfer (integration), and "disintegration" (the reversal of strand transfer). Inhibition was studied by using oligonucleotide substrates with sequences corresponding to the U3 and U5 regions of HIV LTR. In the presence of 20 ng of viral substrate, 50 ng of target substrate, and 4 microM integrase, total inhibition was achieved at equimolar concentrations of the integrase and the antiviral proteins, with EC50 values of about 1 microM. Integration of viral DNA into the host chromosome is a vital step in the replicative cycle of retroviruses, including the AIDS virus. The inhibition of HIV-1 integrase by MAP30 and GAP31 suggests that impediment of viral DNA integration may play a key role in the anti-HIV activity of these plant proteins.

Perianal Complete Remission With Combined Therapy (seton Placement And Anti-tnf Agents) In Crohn's Disease: A Brazilian Multicenter Observational Study.

Perianal fistulizing Crohn's disease is one of the most severe phenotypes of inflammatory bowel diseases. Combined therapy with seton placement and anti-TNF therapy is the most common strategy for this condition. The aim of this study was to analyze the rates of complete perianal remission after combined therapy for perianal fistulizing Crohn's disease. This was a retrospective observational study with perianal fistulizing Crohn's disease patients submitted to combined therapy from four inflammatory bowel diseases referral centers. We analyzed patients' demographic characteristics, Montreal classification, concomitant medication, classification of the fistulae, occurrence of perianal complete remission and recurrence after remission. Complete perianal remission was defined as absence of drainage from the fistulae associated with seton removal. A total of 78 patients were included, 44 (55.8%) females with a mean age of 33.8 (±15) years. Most patients were treated with Infliximab, 66.2%, than with Adalimumab, 33.8%. Complex fistulae were found in 52/78 patients (66.7%). After a medium follow-up of 48.2 months, 41/78 patients (52.6%) had complete perianal remission (95% CI: 43.5%-63.6%). Recurrence occurred in four (9.8%) patients (95% CI: 0.7%-18.8%) in an average period of 74.8 months. Combined therapy lead to favorable and durable results in perianal fistulizing Crohn's disease.

Mudanças no âmbito da testagem anti-HIV no Brasil entre 1998 e 2005

OBJETIVO: Analisar mudanças na realização de teste anti-HIV, as razões alegadas entre as pessoas que foram ou não testadas e o recebimento de aconselhamento. MÉTODOS: Estudos transversais conduzidos com homens e mulheres de 16 a 65 anos, com amostras representativas do Brasil urbano em 1998 (n=3.600) e 2005 (n=5.040). Características sociodemográficas, sexuais, reprodutivas e de experiências de vida e saúde foram consideradas na análise. A avaliação das possíveis diferenças nas distribuições das variáveis baseou-se nos testes qui-quadrado de Pearson e F design-based (±<5%). RESULTADOS: Em 1998, 20,2% dos entrevistados haviam realizado o teste e 33,6% em 2005. Foram testadas 60% das mulheres na faixa 25-34 anos, mas as que iniciaram a vida sexual antes dos 16 anos e reportaram quatro ou mais parceiros sexuais nos cinco anos anteriores à entrevista foram menos testadas. Não se observou aumento significativo da testagem entre homens, exceto para os de 55-65 anos, renda per capita entre 1-3 e 5-10 salários mínimos, aposentados, protestantes históricos e adeptos de cultos afro-brasileiros, moradores da região Norte/Nordeste e os que declararam parceria homo/bissexual ou não tiveram relações sexuais nos cinco anos anteriores à entrevista. Não aumentou a freqüência de testagem entre pessoas auto-avaliadas como sob alto risco para o HIV. Entre as mulheres, a freqüência de testagem pré-natal aumentou e a testagem por trabalho diminuiu entre os homens. Em 2005, metade dos testados não recebeu orientação antes ou após o teste. CONCLUSÕES: Houve expansão desigual na testagem, atingindo principalmente mulheres em idade reprodutiva, adultas e pessoas com melhores condições sociais. A testagem parece estar aumentando no País sem a devida atenção à decisão autônoma das pessoas e sem o provimento de maior e melhor oferta de aconselhamento

Piperamides and their derivatives as potential anti-trypanosomal agents

We describe herein an evaluation of the trypanocidal effect of eight piperamides (1-8) isolated from Piper tuberculatum bearing dihydropyridone, piperidine, and isobutyl moieties against epimastigote forms of Trypanosoma cruzi, the causative agent of Chagas` disease. Based on such results, three hydrogenated and two hydrolyzed derivatives (10-14) were prepared and evaluated as well. The dihydropyridone amides (1-3) displayed higher anti-trypanosomal activity. The (Z)-piplartine (1) showed higher activity with a 50% inhibition concentration (IC(50)) value of 10.5 mu M, almost four times more potent than the positive control, benznidazole (IC(50) = 42.7 mu M), and should be further evaluated as a suitable hit for the design of new antiprotozoal agents.

Disponibilidade de sorologia anti-HIV como um teste voluntário na rotina do atendimento pré-natal em unidades básicas de saúde

São apresentadas, de forma sucinta, as principais etapas cumpridas para a implementação da sorologia anti-HIV no atendimento às gestantes em unidades básicas de saúde. A partir de agosto de 1996, a realização de testes sorológicos para detecção do HIV passou a ser ofertada às gestantes atendidas em unidades básicas de saúde de Ribeirão Preto, SP, integrada a um conjunto de atividades rotineiramente executadas no atendimento pré-natal. Até o final de 1998, o teste sorológico foi aplicado em 68,3% das 17.589 mulheres atendidas em pré-natal, resultando numa positividade de 0,76%.

Central obesity and dietary intake in HIV/AIDS patients

OBJECTIVE: To assess the association between dietary intake and central obesity among people living with HIV/AIDS and receiving highly active antiretroviral therapy. METHODS: A cross-sectional study was conducted involving 223 adult individuals in the city of São Paulo city in 2002. The study population was classified according to central obesity, defined as waist-to-hip ratio >0.95 for men and >0.85 for women. The dietary variables studied were energy consumption (in calories and calories/kilo of body weight), macronutrients (in grams and % of energy intake), total fiber (grams) and fruit and vegetables intake (grams). The potential confounders examined were sex, skin color, age, schooling, income, body mass index, physical activity, smoking habits, peripheral CD4+ T lymphocyte count and length of protease inhibitor use. The multiple logistic regression model was performed in order to evaluate the association between central obesity and dietary intake. RESULTS: The prevalence of central obesity was 45.7% and it was associated with greater consumption of lipids: for every increase of 10g of lipid intake the odds of central obesity increased 1.28 times. Carbohydrate consumption showed negative association (OR=0.93) with central obesity after adjustment for control variables. CONCLUSIONS: The results suggest that the amount of carbohydrates and lipids in the diet, regardless of total energy intake, may modify the chance of developing central obesity in the studied population. Nutritional interventions may be beneficial for preventing central obesity among HIV/AIDS patients.

Mudanças no âmbito da testagem anti-HIV no Brasil entre 1998 e 2005

OBJETIVO: Analisar mudanças na realização de teste anti-HIV, as razões alegadas entre as pessoas que foram ou não testadas e o recebimento de aconselhamento. MÉTODOS: Estudos transversais conduzidos com homens e mulheres de 16 a 65 anos, com amostras representativas do Brasil urbano em 1998 (n=3.600) e 2005 (n=5.040). Características sociodemográficas, sexuais, reprodutivas e de experiências de vida e saúde foram consideradas na análise. A avaliação das possíveis diferenças nas distribuições das variáveis baseou-se nos testes qui-quadrado de Pearson e F design-based (±<5%). RESULTADOS: Em 1998, 20,2% dos entrevistados haviam realizado o teste e 33,6% em 2005. Foram testadas 60% das mulheres na faixa 25-34 anos, mas as que iniciaram a vida sexual antes dos 16 anos e reportaram quatro ou mais parceiros sexuais nos cinco anos anteriores à entrevista foram menos testadas. Não se observou aumento significativo da testagem entre homens, exceto para os de 55-65 anos, renda per capita entre 1-3 e 5-10 salários mínimos, aposentados, protestantes históricos e adeptos de cultos afro-brasileiros, moradores da região Norte/Nordeste e os que declararam parceria homo/bissexual ou não tiveram relações sexuais nos cinco anos anteriores à entrevista. Não aumentou a freqüência de testagem entre pessoas auto-avaliadas como sob alto risco para o HIV. Entre as mulheres, a freqüência de testagem pré-natal aumentou e a testagem por trabalho diminuiu entre os homens. Em 2005, metade dos testados não recebeu orientação antes ou após o teste. CONCLUSÕES: Houve expansão desigual na testagem, atingindo principalmente mulheres em idade reprodutiva, adultas e pessoas com melhores condições sociais. A testagem parece estar aumentando no País sem a devida atenção à decisão autônoma das pessoas e sem o provimento de maior e melhor oferta de aconselhamento.

Metabolic changes associated with antiretroviral therapy in HIV-positive patients

OBJECTIVE: To evaluate metabolic changes associated with highly active antiretroviral therapy (HAART) in HIV-positive patients, and to identify risk factors associated. METHODS: Retrospective study that included 110 HIV-positive patients who where on HAART in the city of Porto Alegre (Southern Brazil) between January 2003 and March 2004. Data on demographic variables, cigarette smoking, diabetes mellitus, cholesterol and triglyceride levels, stage of HIV infection, antiretroviral therapy and HCV coinfection were collected. General linear models procedure for repeated measures was used to test the interaction between HAART and HCV coinfection or protease inhibitor treatment. RESULTS: Total cholesterol, triglycerides, and glucose levels significantly increased after receiving HAART (p<0.001 for all variables), but no interaction with protease inhibitors was seen for total cholesterol, glucose and triglyceride levels (interaction treatment*protease inhibitors p=0.741, p=0.784, and p=0.081, respectively). An association between total cholesterol levels and HCV coinfection was found both at baseline and follow-up (effect of HCV coinfection, p=0.011). Glucose levels were increased by HAART (treatment effect, p=0.036), but the effect was associated to HCV coinfection (treatment*HCV effect, p=0.018). Gender, smoking habit, intravenous drug use and age were not significantly associated with cholesterol, triglyceride and glucose changes. CONCLUSIONS: HCV-infected patients at baseline were significantly less likely to develop hypercholesterolemia. The results provide further evidence of the role of HAART for the development of metabolic disturbances.

Resultado do teste rápido anti-HIV após o parto: uma ameaça à amamentação ao nascimento

OBJETIVO: Analisar fatores associados à não-amamentação na primeira hora de vida, sobretudo a influência do momento do resultado do teste rápido anti-HIV. MÉTODOS: Estudo de coorte, sendo o ponto inicial a submissão ao teste rápido e o final a primeira mamada do bebê. A população estudada incluiu 944 parturientes submetidas ao teste rápido anti-HIV, com resultado negativo, em 2006, nos cinco hospitais amigos da criança do Sistema de Gestação de Alto Risco no município do Rio de Janeiro, RJ. Entrevistadoras treinadas obtiveram dados do laboratório e do prontuário e no pós-parto aplicaram questionário para entrevista às mães. O modelo multinível foi adotado para analisar a influência de características sociodemográficas, de assistência pré-natal e ao parto sobre a não-amamentação na primeira hora de vida. RESULTADOS: Dentre as participantes, apenas 15,6% receberam seu resultado antes do parto, 30,8% depois do parto e 53,6% ainda desconheciam o resultado ao ser entrevistada. A prevalência de não-amamentação na primeira hora de vida foi de 52,5% (IC 95%: 49,3;55,8). Após ajuste, o recebimento do resultado do teste rápido após o parto dobrou o risco da não-amamentação na primeira hora de vida (RR=2,06; IC 95%: 1,55;2,75). Outros fatores de risco foram: cor não branca, renda materna de um salário mínimo ou menos, parto cesáreo, mãe não querer amamentar o bebê ao nascimento e mãe referir que a equipe hospitalar não a escutava. O desconhecimento da realização do teste rápido anti-HIV pela mãe se mostrou como fator de proteção. CONCLUSÕES: O principal fator de risco para a não-amamentação na primeira hora de vida foi o recebimento do resultado do teste rápido após o parto. O teste anti-HIV deve ser amplamente disponibilizado no pré-natal e o teste rápido deve ser realizado sob indicação, na admissão, com busca ativa e pronta comunicação do resultado à mulher.

Demandas e expectativas de usuários de centro de testagem e aconselhamento anti-HIV

OBJETIVO: Analisar características, demandas e expectativas de usuários de um centro de testagem e aconselhamento anti-HIV. PROCEDIMENTOS METODOLÓGICOS: Pesquisa qualitativa realizada com 32 usuários de centro de testagem e aconselhamento do estado de Minas Gerais, de novembro de 2005 a março de 2006. Utilizou-se a técnica de entrevista aberta semi-estruturada e uma adaptação do método de análise de conteúdo, empregando-se a modalidade temática. ANÁLISE DOS RESULTADOS: A falta de conhecimento do serviço, a dificuldade de se perceber vulnerável à infecção, as justificativas por não pertencer aos grupos de risco, o receio do constrangimento e de um atendimento precário surgiram como importantes limitações de acesso aos centros de testagem e aconselhamento. CONCLUSÕES: No discurso dos usuários, foi identificado um paradoxo entre o aspecto participativo na superação da vulnerabilidade e a busca de soluções pragmáticas de exclusão do risco. Suas demandas sinalizaram estratégias que contenham: qualidade da informação prestada, acesso ao serviço e aos discursos de prevenção e promoção da saúde.

Direct treatment costs of HIV/AIDS in Portugal

OBJECTIVE To analyze the direct medical costs of HIV/AIDS in Portugal from the perspective of the National Health Service. METHODS A retrospective analysis of medical records was conducted for 150 patients from five specialized centers in Portugal in 2008. Data on utilization of medical resources during 12 months and patients’ characteristics were collected. A unit cost was applied to each care component using official sources and accounting data from National Health Service hospitals. RESULTS The average cost of treatment was 14,277 €/patient/year. The main cost-driver was antiretroviral treatment (€ 9,598), followed by hospitalization costs (€ 1,323). Treatment costs increased with the severity of disease from € 11,901 (> 500 CD4 cells/µl) to € 23,351 (CD4 count ≤ 50 cells/ µl). Cost progression was mainly due to the increase in hospitalization costs, while antiretroviral treatment costs remained stable over disease stages. CONCLUSIONS The high burden related to antiretroviral treatment is counterbalanced by relatively low hospitalization costs, which, however, increase with severity of disease. The relatively modest progression of total costs highlights that alternative public health strategies that do not affect transmission of disease may only have a limited impact on expenditure, since treatment costs are largely dominated by constant antiretroviral treatment costs.

Strategies for price reduction of HIV medicines under a monopoly situation in Brazil

ABSTRACT OBJECTIVE To analyze Government strategies for reducing prices of antiretroviral medicines for HIV in Brazil. METHODS Analysis of Ministry of Health purchases of antiretroviral medicines, from 2005 to 2013. Expenditures and costs of the treatment per year were analyzed and compared to international prices of atazanavir. Price reductions were estimated based on the terms of a voluntary license of patent rights and technology transfer in the Partnership for Productive Development Agreement for atazanavir. RESULTS Atazanavir, a patented medicine, represented a significant share of the expenditures on antiretrovirals purchased from the private sector. Prices in Brazil were higher than international references, and no evidence was found of a relationship between purchase volume and price paid by the Ministry of Health. Concerning the latest strategy to reduce prices, involving local production of the 200 mg capsule, the price reduction was greater than the estimated reduction. As for the 300 mg capsule, the amounts paid in the first two years after the Partnership for Productive Development Agreement were close to the estimated values. Prices in nominal values for both dosage forms remained virtually constant between 2011 (the signature of the Partnership for Productive Development Agreement), 2012 and 2013 (after the establishment of the Partnership). CONCLUSIONS Price reduction of medicines is complex in limited-competition environments. The use of a Partnership for Productive Development Agreement as a strategy to increase the capacity of local production and to reduce prices raises issues regarding its effectiveness in reducing prices and to overcome patent barriers. Investments in research and development that can stimulate technological accumulation should be considered by the Government to strengthen its bargaining power to negotiate medicines prices under a monopoly situation.

The effect of antioxidant properties of aqueous garlic extract and Nigella sativa as anti-schistosomiasis agents in mice

The aim of this study was to assess the antioxidant and anti-schistosomal activities of the garlic extract (AGE) and Nigella sativa oil (NSO) on normal and Schistosoma mansoni-infected mice. AGE (125 mg kg-1, i.p.) and NSO (0.2 mg kg-1, i.p.) were administrated separately or in combination for successive 28 days, starting from the 1st day post infection (pi). All mice were sacrificed at weeks 7 pi. Hematological and biochemical parameters including liver and kidney functions were measured to assess the progress of anemia, and the possibility of the tissue damage. Serum total protein level, albumin, globulin and cholesterol were also determined. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in the liver tissues as biomarkers for oxidative and reducing status, respectively. The possible effect of the treatment regimens on Schistosoma worms was evaluated by recording percentage of the recovered worms, tissue egg and oogram pattern. Result showed that, protection with AGE and NSO prevented most of the hematological and biochemical changes and markedly improved the antioxidant capacity of schistosomiasis mice compared to the infected-untreated ones. In addition, remarkable reduction in worms, tissue eggs and alteration in oogram pattern were recorded in all the treated groups. The antioxidant and antischistosomal action of AGE and NSO was greatly diverse according to treatment regimens. These data point to these compounds as promising agents to complement schistosomiasis specific treatment.