Evaluation of the genotypic resistance profile of HIV-1 to antiretroviral drugs in children and adolescents in therapeutic failure in Goiás in the period 2003 to 2015

Submitted by Luciana Ferreira ([email protected]) on 2017-01-11T10:12:07Z No. of bitstreams: 2 Dissertação - Maly de Albuquerque - 2016.pdf: 6439993 bytes, checksum: ac49fa77e013cea8bc3ea3be9901914b (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Approved for entry into archive by Luciana Ferreira ([email protected]) on 2017-01-11T10:14:41Z (GMT) No. of bitstreams: 2 Dissertação - Maly de Albuquerque - 2016.pdf: 6439993 bytes, checksum: ac49fa77e013cea8bc3ea3be9901914b (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Made available in DSpace on 2017-01-11T10:14:41Z (GMT). No. of bitstreams: 2 Dissertação - Maly de Albuquerque - 2016.pdf: 6439993 bytes, checksum: ac49fa77e013cea8bc3ea3be9901914b (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-12-20Objective: The aims of this study were to detect and identify drug resistance mutations through genotyping related to antiretroviral (ARV) resistance in children and adolescents infected with HIV-1 and with therapeutic failure. Methods: This was a descriptive study based on a retrospective cohort of HIV-infected children and adolescents diagnosed between 1992 and 2013. The pattern of ARV resistance mutations was analyzed in 65 children and adolescents, in therapeutic failure and followed up in a reference pediatric infectious disease clinic since diagnosis. A total of 92 genotypic resistance tests were carried out from 2003 to 2015. Genotypic tests were collected at the Central Laboratory (LACEN) and performed by the RENAGENO laboratory. For the interpretation of resistance the ARV algorithm was used (RENAGENO’s algorithm version 13th, 2015) and the Stanford’s algorithm (Stanford HIV drug resistance database, 2015). The study protocol’s was approved by the ethics committee of the HC / UFG and HDT / SES. Statistical analysis was performed with the software Microsoft Excel version 2010 and Statistical Package for the Social Sciences (SPSS®) 20.0 for Windows. Descriptive and inferential analyzes (t-Student and U-Mann-Whitney tests) were performed, considering the level of significance at 5%. Results: The sample consisted of 65 children and adolescents, with median age at diagnosis of 29.2 months (range from 2 months to 120 months); the majority was female (36/65). A total of 64 (98.5%) patients acquired HIV vertical transmission. Approximately 55% of the patients presented with severe immunosuppression at diagnosis of HIV, and 33% belonged to class B or C, according to the CDC-1994 clinical and immunological classification. The median baseline CD4 lymphocyte count was 921 cells/mm3. HIV viral load, before starting HAART, showed a median of 678,998 copies (log 5.83). At the time of first genotyping, CD4 ranged from 1 to 2940 cells/mm3, with a median of 608 cells/mm3, with a median of 40,548 copies/mL (log 4,60). Most mutations were found in the NRTI class (98.5%), followed by NNRTI (75.4%) and PI (44.6%). The most frequent mutations in the NRTI class were T215 codons (83.1%), with prevalence of T215YF (69.2%), M184V (69.3%), and M41L (52.3%). The most observed mutations in the NNRTI class were K103N / S (40.0%), 190A / S (30.8%), 101E / P / Q (23.1%). Mutations associated with resistance in protease occurred mainly in codons 54, 82 and 46, with rates of 35.4%; 32.3%; 27.7%; respectively. Resistance to more than one class occurred in 41.5%, 12.3% and 35.4% with the combination of NRTIs and NRTIs, ITRN + IP / r, and with the three NRTI + NRTI + IP classes respectively. After rescue therapy, approximately 90% of the patients analyzed had viral suppression, with HIV viral RNA levels below the detection limits (<50 or 40 copies) after 24 weeks of change in the combined antiretroviral regimen (P <0.001). Immunological response resulted in benefit, with significant elevation in CD4 + T cell count (P <0.001). Conclusions: Our study provided relevant information on the results of the genotypic resistance test after failure of long-term ARV therapy in children and adolescents infected with HIV. There were high mutation rates in all antiretroviral classes tested. Rescue therapy guided by the genotypic test provided high rates of viral suppression. Thus, the genotype test emphasizes the possibility of adequately composing an ARV regimen, with a high genetic barrier, using the new drugs and new classes of ARV drugs, with the objective of avoiding the therapeutic failure after rescue and preventing the accumulation of other mutations related to drug resistance.Objetivo: Analisar, por meio do teste genotípico, o perfil de mutações aos antirretrovirais em crianças e adolescentes infectados pelo HIV-1 com falha terapêutica. Métodos: Trata-se de um estudo descritivo, de uma coorte retrospectiva de crianças e adolescentes infectados pelo HIV, diagnosticadas entre 1992 e 2013. Foi analisado o padrão de mutações de resistência aos antirretrovirais (ARV) em 65 crianças e adolescentes, em falha terapêutica e acompanhados no ambulatório de infectologia pediátrica do HDT desde o diagnóstico. Foram avaliados 92 testes de resistência genotípica realizados no período de 2003 a 2015. Os testes genotípicos foram coletados no Laboratório Central (LACEN) e executados pelo laboratório da RENAGENO, através do Programa Nacional DST e Aids do Ministério da Saúde. Para a interpretação de resistência aos ARV foram utilizados o algoritmo Brasileiro (RENAGENO - Algoritmo versão 13, 2015) e o algoritmo The Stanford University HIV Drug Resistance Database (Stanford HIV drug resistance database, 2015). O trabalho foi aprovado pelo comitê de ética do HC/UFG e do HDT/SES. A análise estatística foi realizada com os softwares Microsoft Excel versão 2010 e Statistical Package for the Social Sciences (SPSS®) 20.0 para Windows. Análises descritivas e inferenciais (testes t-Student e U-Mann-Whitney) foram realizadas, considerando o nível de significância em 5%. Resultados: A amostra foi constituída por 65 crianças e adolescentes, com mediana de idade ao diagnóstico de 29,2 meses (variação de 2 meses a 120 meses); a maioria era do sexo feminino (36/65). Um total de 64 (98,5%) pacientes adquiriu a infecção por transmissão vertical. Aproximadamente 55% dos pacientes apresentavam imunossupressão grave ao diagnóstico de HIV, e 33% pertenciam a classe B ou C, conforme a classificação clínica e imunológica do CDC-1994. A mediana de contagem basal de linfócitos CD4 foi 921 células/mm3. A carga viral do HIV, antes do início da TARV, demonstrou mediana de 678.998 cópias/mL (log 5,83). No momento da coleta do teste de genotipagem, o valor do CD4 variou de 1 a 2940 células/mm3, com mediana de 608 células/mm3, sendo que a carga viral teve mediana de 40.548 cópias/mL (log 4,60). Foram encontradas mais frequentemente mutações na classe de ITRN (98,46%), seguida pela ITRNN (75,4%) e IP (44,6%). As mutações mais frequentes na classe de ITRN foram nos códons T215 (83,1%), com prevalência da T215YF (69,2%), M184V (69,3%), M41L (52,3%). As mutações mais observadas na classe dos ITRNN foram K103N/S (40,0%), 190A/S (30,8%), 101E/P/Q (23,1%). As mutações associadas à resistência na protease ocorreram principalmente nos códons 54, 82 e 46, apresentando taxas de 35,4%, 32,3% e 27,7%, respectivamente. A resistência a mais de uma classe ocorreu em 41,5%, 12,3% e 35,4% com a associação de ITRN + ITRNN, ITRN + IP/r e nas três classes ITRN + ITRNN + IP, respectivamente. Após a terapia de resgate, observou-se que aproximadamente 90% dos pacientes analisados atingiram supressão viral, com níveis de RNA viral do HIV abaixo do limites de detecção (<50 ou 40 cópias) após 24 semanas da mudança do esquema antirretroviral combinado (cARV) (P<0,001). A resposta imunológica resultou em benefício, com elevação na contagem de células T CD4+ (P<0,001). Conclusões: Este estudo forneceu informações relevantes nos resultados do teste genotípico de resistência após falha de terapia ARV a longo prazo em crianças e adolescentes infectados perinatalmente pelo HIV. Houve elevada taxa de mutação em todas as classes de antirretrovirais analizadas. A terapia de resgate guiada pelo teste genotípico proporcionou elevadas taxas de supressão viral. Dessa forma, a realização do teste genotípico reforça a possibilidade de compor adequadamente um regime ARV, com alta barreira genética, utilizando as novas drogas e novas classes de drogas ARV, para evitar a falha terapêutica após o resgate e prevenir acúmulo de outras mutações de resistência às drogas

Análise da taxa de transmissão vertical do HIV e fatores de risco materno-fetais em crianças expostas nascidas em centro de referência do estado de Goiás

Objetivos: Estimar a taxa de transmissão vertical do HIV e os fatores de risco materno-fetais em crianças nascidas em 2015 em seguimento durante os anos de 2015 a 2017 no maior centro de referência para tratamento para HIV do estado de Goiás. Métodos: Estudo de coorte retrospectivo de 111 crianças expostas ao HIV nascidas em 2015 de mães HIV positivas. Resultados: Entre as mães, 85 (92,4%) utilizaram TARV durante a gestação. Das 92 crianças que mantiveram seguimento, 4 (4,34%) adquiriram infecção perinatal pelo HIV. 81 (88%) recém-nascidos fizeram uso de profilaxia antirretroviral. Um fator protetor importante de transmissão vertical do HIV foi a profilaxia antirretroviral do RN (OR = 0,02; IC 95%: 0,00-0,56; p = 0,04). Outros fatores investigados, como uso de TARV durante a gestação, não foram estatisticamente significativas para risco. Conclusão: A taxa de transmissão vertical do HIV ainda se encontra elevada no estado de Goiás e os desafios para sua prevenção consistem na perda de seguimento e falhas nas medidas estratégicas.Objectives: To estimate the mother-to-child transmission rate of HIV and the maternal-fetal risk factors in children born in 2015 in follow-up during the years 2015 to 2017 in the largest reference center for HIV treatment in the state of Goiás. Methods: Retrospective cohort study of 111 HIV-exposed children born in 2015 of HIV-positive mothers, with 19 follow-up losses. Results: Among the mothers, 85 (92.4%) used ART during pregnancy. Of the 92 children who maintained follow-up, 4 (4.34%) acquired perinatal HIV infection. 81 (88%) newborns used antiretroviral prophylaxis. An important protective factor for vertical HIV transmission was neonatal prophylaxis (OR:0.02, 95%; CI: 0.00-0.56, p = 0.04). Other investigated factors, such as ART during pregnancy, were not statistically significant for risk. Conclusion: The vertical transmission rate of HIV is still high in the State of Goiás and the challenges for its prevention consist in the loss of follow-up and failures in the strategic measures

Resposta de testes de hipersensibilidade tardia utilizando PPD e outros antígenos em crianças e adolescentes saudáveis e infectados pelo HIV-1 e vacinados com BCG

INTRODUÇÃO: A contagem de células CD4+ representa marcador da resposta imune celular em pacientes infectados pelo HIV-1. Testes cutâneos de hipersensibilidade tardia (DTH) podem ser empregados para avaliar in vivo respostas celulares a antígenos comuns. MÉTODOS: DTH para derivado proteico purificado de tuberculina (PPD), esporotriquina, tricofitina, candidina e estreptoquinase/estreptodornase foram realizados. Foram testados crianças/adolescentes infectados pelo HIV-1 (n=36) e indivíduos saudáveis (n=56), soronegativos para HIV-1/HIV-2 pareados por sexo-idade, todos com cicatriz vacinal por BCG. Teste exato de Fisher foi aplicado (p<0,05). RESULTADOS: Entre as crianças/adolescentes infectados pelo HIV-1, mediana de idade=8,1 anos; 20/36 eram do sexo masculino; 35 casos de transmissão vertical; 34 casos de AIDS sob terapia antirretroviral; mediana de carga viral = 3.04lc10 cópias/ml; mediana de contagem de células CD4+ = 701 células/&#956;l. Entre os infectados e saudáveis a reatividade DTH a pelo menos um dos antígenos foi, respectivamente, 25% (9/36) e 87,5% (49/56) (p<0,001). Reatividade à candidina predominou nos infectados (8/36, 22%) e ao PPD nos indivíduos saudáveis (40/56, 71,4%). A reatividade ao PPD entre infectados foi de 8,3% (p<0,01). A mediana da induração ao PPD foi 2,5mm (variação: 2-5mm) entre infectados e 6,0mm (variação: 3-15mm) entre os saudáveis. Não observamos correlação entre positividade ao PPD e idade. No grupo de infectados, não observamos correlação entre contagens de células CD4+ e reatividade ao DTH. CONCLUSÕES: Respostas DTH significativamente diminuídas, incluindo a reatividade ao PPD foram observadas em crianças/adolescentes infectados pelo HIV-1 comparadas com controles saudáveis, provavelmente refletindo doença avançada e supressão da imunidade mediada por células T

Drug-Coated Balloon Treatment of Femoropopliteal Lesions for Patients With Intermittent Claudication and Ischemic Rest Pain: 2-Year Results From the IN.PACT Global Study

Objectives: The IN.PACT Global Study is the largest prospective, multicenter, independently adjudicated trial to evaluate a paclitaxel drug-coated balloon in patients with lifestyle-limiting claudication and/or ischemic rest pain due to atherosclerotic disease of the femoropopliteal artery and includes complex lesions beyond what are typically included in randomized controlled trials. Background: Randomized controlled trials have demonstrated the safety and efficacy of drug-coated balloons for the treatment of Trans-Atlantic Inter-Society Consensus Document II A and B lesions, but there is a need for large-scale prospective studies to evaluate a broader range of lesions. Methods: The IN.PACT Global Study enrolled 1,535 subjects, and 1,406 (1,773 lesions) were included in the pre-defined clinical cohort analysis. Freedom from clinically driven target lesion revascularization was evaluated at 24 months. The safety composite endpoint was freedom from device- and procedure-related death through 30 days and freedom from target limb major amputation and clinically driven target vessel revascularization within 24 months. Results: Mean lesion length was 12.1 cm, 35.5% were total occlusions, and 18.0% had in-stent restenosis. Freedom from clinically driven target lesion revascularization at 24 months was 83.3%, the composite safety endpoint was met in 81.7%, the 2-year all-cause mortality rate was 7.0%, and the major target limb amputation rate was 0.7%. Increased lesion length and the presence of de novo in-stent restenosis or coronary artery disease were associated with increased risk for clinically driven target lesion revascularization by 24 months. Conclusions: This real-world study of femoropopliteal artery disease treatment with drug-coated balloons confirmed positive findings reported from more strictly designed randomized controlled trials and showed that outcomes are durable in this population up to 2 years after treatment. (IN.PACT Global Clinical Study; NCT01609296

Safety and outcome of revascularization treatment in patients with acute ischemic stroke and COVID-19: the Global COVID-19 Stroke Registry

Background and ObjectivesCOVID-19-related inflammation, endothelial dysfunction, and coagulopathy may increase the bleeding risk and lower the efficacy of revascularization treatments in patients with acute ischemic stroke (AIS). We aimed to evaluate the safety and outcomes of revascularization treatments in patients with AIS and COVID-19.MethodsThis was a retrospective multicenter cohort study of consecutive patients with AIS receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021 tested for severe acute respiratory syndrome coronavirus 2 infection. With a doubly robust model combining propensity score weighting and multivariate regression, we studied the association of COVID-19 with intracranial bleeding complications and clinical outcomes. Subgroup analyses were performed according to treatment groups (IVT-only and EVT).ResultsOf a total of 15,128 included patients from 105 centers, 853 (5.6%) were diagnosed with COVID-19; of those, 5,848 (38.7%) patients received IVT-only and 9,280 (61.3%) EVT (with or without IVT). Patients with COVID-19 had a higher rate of symptomatic intracerebral hemorrhage (SICH) (adjusted OR 1.53; 95% CI 1.16-2.01), symptomatic subarachnoid hemorrhage (SSAH) (OR 1.80; 95% CI 1.20-2.69), SICH and/or SSAH combined (OR 1.56; 95% CI 1.23-1.99), 24-hour mortality (OR 2.47; 95% CI 1.58-3.86), and 3-month mortality (OR 1.88; 95% CI 1.52-2.33). Patients with COVID-19 also had an unfavorable shift in the distribution of the modified Rankin score at 3 months (OR 1.42; 95% CI 1.26-1.60).DiscussionPatients with AIS and COVID-19 showed higher rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than contemporaneous non-COVID-19 patients receiving treatment. Current available data do not allow direct conclusions to be drawn on the effectiveness of revascularization treatments in patients with COVID-19 or to establish different treatment recommendations in this subgroup of patients with ischemic stroke. Our findings can be taken into consideration for treatment decisions, patient monitoring, and establishing prognosis.Paroxysmal Cerebral Disorder

Oral Apixaban for the Treatment of Acute Venous Thromboembolism

BACKGROUND: Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism. METHODS: In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding. RESULTS: The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201)

Stress neuropeptide levels in adults with chest pain due to coronary artery disease: potential implications for clinical assessment

: Substance P (SP) and neuropeptide Y (NPY) are neuropeptides involved in nociception. The study of biochemical markers of pain in communicating critically ill coronary patients may provide insight for pain assessment and management in critical care. Purpose of the study was to to explore potential associations between plasma neuropeptide levels and reported pain intensity in coronary critical care adults, in order to test the reliability of SP measurements for objective pain assessment in critical care