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The SARS-CoV-2, causal agent of the COVID-19 current pandemic, is suffering mutations as a consequence of its evolutive cycle, what has originated different genetic variants that have been grouped in two categories: worrying (alpha or British, beta or South African, gamma or Brazilian and delta or Indian) and of interest (lamdba, mu, epsilon, eta, iota, kappa, zed, theta); these categories bear clinical implications in the transmissibility, virulence and resistance from SARS-CoV-2 to the natural and acquired immunity, what represents a serious challenge in health services worldwide. These genetic variants are described in this work, with emphasis in its probable clinical impact, and the possibility that other variants could appear is also explained, as natural phenomenon in the evolution of viruses.

[ES] El sistema hepatobiliar forma parte del aparato digestivo e incluye el hígado, la vesícula y las vías biliares. Se trata de un sistema fundamental para mantener la homeostasis del organismo, al excretar productos de desecho lipófilos a través de la bilis y detoxificar la sangre proveniente del intestino, metabolizando y eliminando sustancias antes de que pasen a la circulación sistémica. Después de la piel y junto con el cerebro, el hígado es el órgano sólido más grande del organismo, con un peso aproximado de 1,5 kg en adultos. Recibe una irrigación sanguínea dual: casi un 80% de la sangre proviene de la vena porta, mientras que el 20% restante es sangre oxigenada que emana de la arteria hepática. La sangre portal procede del estómago, intestino, páncreas y bazo, y contiene sustancias que serán filtradas por el hígado para su metabolismo y/o eliminación. Morfológicamente, el ligamento falciforme divide el hígado en dos lóbulos principales: el derecho y el izquierdo. No obstante, desde un punto de vista funcional, existen ocho segmentos hepáticos que reciben riego sanguíneo de ramas provenientes de la vena porta y la arteria hepática. Paralelamente, en cada uno de estos segmentos la sangre es devuelta a una rama de la vena hepática y la bilis se libera al conducto biliar. Por otra parte, el sistema biliar complementa la función del hígado, concentrando, almacenando y conduciendo la bilis hacia el duodeno. El árbol biliar emerge de los dúctulos biliares o canales de Hering, que representan la unión fisiológica entre el sistema canalicular hepatocitario y el sistema biliar colangiolar. Estos convergen en los conductos biliares intrahepáticos y, posteriormente, en los extrahepáticos. Entre estos últimos se encuentra la vesícula biliar que, al contrario que el resto del tracto biliar, no aparece en todos los vertebrados.

Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Immunoparasitologia. Salvador, BA, Brasil University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil / Instituto Butantan. Imunologia Viral. Sao Paulo, SP, Brasil Several new direct-acting antiviral (DAA) drugs are in development for chronic hepatitis C viral (HCV) infection, and NS3-NS4A serine protease and the NS5B RNA-dependent RNA polymerase have been the major targets. HCV variants displaying drug-resistant phenotypes have been observed both in vitro and during clinical trials. Our aim was to characterize amino acid changes at positions previously associated with resistance in protease (NS3) and polymerase (NS5B) regions from treatment-naïve HCV patients infected with genotypes 1a, 1b and 3a. All 1383 NS3 protease sequences (genotype 1a = 680, 1b = 498 and 3a = 205) and 806 NS5B polymerase sequences (genotypes 1a = 471, 1b = 329, 3a = 6) were collected from Los Alamos databank. Genotype 3a protease sequences showed the typical low-level resistance mutation V36L. NS3 sequences from other genotypes presented mutations on positions 36, 39, 41, 43, 54, 80, 109, 155 and 168 in a frequency lower than 2%, except for the mutation Q80R found in 35% of genotype 1a isolates. Polymerase sequences from genotype 3a patients showed five typical mutations: L419I, I424V, I482L, V499A and S556G. Two positions presented high polymorphism in the NS5B region from genotype 1a (V499A) and genotype 1b (C316N) subjects. Our results demonstrated a natural profile of genotype 3a that can be associated with the pre-existence of HCV variants resistant to first-generation protease inhibitors and to non-nucleoside polymerase inhibitors. Likewise, genotype 1b isolates and genotype 1a sequences exhibited pre-existing mutations associated with resistance to Palm II and Thumb I polymerase inhibitors, respectively.

Introducción: En Colombia los tratamientos para el virus de inmunodeficiencia humana, consumen gran parte del presupuesto en salud, debido a que el costo es directamente proporcional al tiempo de supervivencia del paciente, por esto los tratamientos más eficaces no están al alcance de toda la población. Un eventual fracaso virológico implica un detrimento en la salud del paciente y, pérdida de recursos asociado a costos del tratamiento. Objetivo: Mostrar mediante un modelo de pronóstico los sobrecostos que genera la falta de adherencia y las mutaciones del virus de inmunodeficiencia humana, que confiere la resistencia de los tratamientos antivirales, así como la eficiencia del tratamiento a pacientes con infección por el mismo. Métodos: Estudio observacional, descriptivo y retrospectivo, muestra de 64 resultados de genotipificación del virus realizada a pacientes en una IPS especializada en atención a personas que viven con infección por el virus de inmunodeficiencia, el cual seleccionó los casos que cumplían los criterios del estudio según los resultados del instrumento aplicado. Resultados: Se determinó que el tiempo de tratamiento y el tiempo de atención en la IPS, no ayudan a pronosticar mutaciones que generen resistencia a los medicamentos antirretrovirales. Además, que la exposición al antiretroviral, en cualquier caso, va a generar algún tipo de mutaciones que generan resistencia al mismo, esto indica que, si se desea pronosticar el costo del tratamiento para ésta EPS, las variables predictoras serán X1= tipo de tratamiento recibido, X2= preferencia sexual y X3= edad. Conclusiones: El costo es imprescindible en la Administración en Salud, fue una de las variables más importantes estudiadas. Se encontró que el factor adherencia es inverso al costo del tratamiento, entre más adherente sea el paciente, menor será el costo. Introduction: Treatments for the human immunodeficiency virus and antiretroviral drugs in Colombia, consume a large part of the health budget, because the cost is directly proportional to the survival time of the patient, so the most effective treatments are within reach of a small part of the population. A possible virological failure implies a detriment in the health of the patient and also, loss of resources associated to the treatment costs. Objective: Using a through a prognostic model, to show the cost overruns caused by lack of adherence and mutations of the HIV virus, which may confer resistance to antiviral treatments to patients with HIV infection. Methods: An observational, descriptive and retrospective study was accomplished with a sample of 64 results of genotyping of the virus carried out on patients at an IPS specialized in comprehensive care for people infected with the immunodeficient virus. It were selected the cases which fulfilled the criteria of the study, according to the results of the instrument applied. Subsequently, the information was analyzed crossing the variables, to describe the behavior. Results: It was determined that the time of treatment and the time of attention in the IPS, do not help to predict mutations that generate resistance to antiretroviral drugs. In addition, it was demonstrated that exposure to ART in any case, will generate some type of mutations that can generate resistance to ART. This indicates that if you want to predict the cost of treatment for this EPS, the predictor variables would be X1= the type of treatment received, X2= Sexual preference and X3= Age. Conclusions: Cost is essential in Health Administration, for which it was one of the most important variables in the study, therefore within the descriptive study it was found that the adherence factor is inverse to the cost of treatment, thereupon, the more adherent be the patient, the lower the cost. 2019-08-01 06:01:01: Script de automatizacion de embargos. info:eu-repo/date/embargoEnd/2019-04-03 Universidad del Rosario

OBJECTIVE: To describe the virological characteristics of the influenza strains circulating in Argentina in 2005-2008 and to assess the prevalence of antiviral resistance. METHODS: On the basis of their geographical spread and prevalence, influenza A and B isolates grown in Madin-Darby canine kidney cells were selected after antigenic and genomic characterization to be analyzed for antiviral resistance by enzymatic assay and pyrosequencing. Amantadine susceptibility was evaluated by pyrosequencing for known resistance markers on 45 strains of influenza A. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay of 67 influenza A and 46 influenza B strains, some of which were further analyzed by sequencing the neuraminidase gene. RESULTS: Resistance to amantadine was observed only on A(H3N2) strains (29/33); all of them carried the mutation S31N in their M2 sequence. Oseltamivir resistance was observed in 12 (34.3%) of the 35 A(H1N1) strains from 2008; all of them carried the mutation H275Y in their neuraminidase sequence. All these viruses remained sensitive to zanamivir. CONCLUSIONS: This study describes a high incidence of amantadine-resistant influenza A(H3N2) viruses since 2006 and an unprecedented increase in oseltamivir resistance detected only in influenza A(H1N1) viruses isolated in 2008. Influenza A and B viruses were more sensitive to oseltamivir than to zanamivir, and influenza A viruses were more sensitive to both neuraminidase inhibitors than the influenza B viruses. The national data generated and analyzed in this study may help increase knowledge about influenza antiviral drug resistance, which is a problem of global concern.OBJETIVO: Describir las características virológicas de las cepas de virus de la gripe que circulaban en la Argentina entre el 2005 y el 2008, y evaluar la prevalencia de la resistencia a los antivíricos. MÉTODOS: Según su diseminación geográfica y su prevalencia, se seleccionaron aislados de gripe A y B cultivados en células renales caninas de Madin-Darby después de su caracterización antigénica y genómica, y se analizó su resistencia a los antivíricos mediante análisis enzimático y pirosecuenciación. La sensibilidad a la amantadina se evaluó por pirosecuenciación para los marcadores conocidos de resistencia en 45 cepas de gripe A. La sensibilidad al oseltamivir y al zanamivir se evaluó mediante análisis enzimático de 67 cepas de gripe A y 46 cepas de gripe B, algunas de las cualesse analizaron en mayor profundidad mediante la secuenciación del gen de la neuraminidasa. RESULTADOS: Se observó resistencia a la amantadina solo en las cepas de gripe A (H3N2) (29/33); todas ellas tenían la mutación S31N en su secuencia de M2. Se observó resistencia al oseltamivir en 12 (34,3%) de las 35 cepas de gripe A (H1N1) aisladas en el 2008; todas ellas tenían la mutación H275Y en su secuencia de neuraminidasa. Todos estos virus conservaron su sensibilidad al zanamivir. CONCLUSIONES: En este estudio se describe una incidencia elevada del virus de la gripe A (H3N2) resistente a la amantadina desde el 2006 y un aumento sin precedentes de la resistencia al oseltamivir detectada solo en los virus de la gripe A (H1N1) aislados en el 2008. Los virus de la gripe A y B fueron más sensibles al oseltamivir que al zanamivir y los virus de la gripe A fueron más sensibles a ambos inhibidores de la neuraminidasa que los virus de la gripe B. Los datos nacionales generados y analizados en este estudio pueden ayudar a aumentar los conocimientos acerca de la resistencia a los fármacos antivíricos dirigidos contra el virus de la gripe, lo que es un motivo de preocupación mundial.

OBJECTIVE: To assess human immunodeficiency virus (HIV) diversity and the prevalence of transmitted drug resistance (TDR) in Guatemala. METHODS: One hundred forty-five antiretroviral treatment-naïve patients referred to the Roosevelt Hospital in Guatemala City were enrolled from October 2010 to March 2011. Plasma HIV pol sequences were obtained and TDR was assessed with the Stanford algorithm and the World Health Organization (WHO) TDR surveillance mutation list. RESULTS: HIV subtype B was highly prevalent in Guatemala (96.6%, 140/145), and a 2.8% (4/145) prevalence of BF1 recombinants and 0.7% (1/145) prevalence of subtype C viruses were found. TDR prevalence for the study period was 8.3% (12/145) with the Stanford database algorithm (score > 15) and the WHO TDR surveillance mutation list. Most TDR cases were associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (83.3%, 10/12); a low prevalence of nucleoside reverse transcriptase inhibitors and protease inhibitors was observed in the cohort (< 1% for both families). Low selection of antiretroviral drug resistance mutations was found, except for NNRTI-associated mutations. Major NNRTI mutations such as K101E, K103N, and E138K showed higher frequencies than expected in ART-naïve populations. Higher literacy was associated with a greater risk of TDR (odds ratio 4.14, P = 0.0264). CONCLUSIONS: This study represents one of the first efforts to describe HIV diversity and TDR prevalence and trends in Guatemala. TDR prevalence in Guatemala was at the intermediate level. Most TDR cases were associated with NNRTIs. Further and continuous TDR surveillance is necessary to gain more indepth knowledge about TDR spread and trends in Guatemala and to optimize treatment outcomes in the country.OBJETIVO: Evaluar la diversidad del virus de la inmunodeficiencia humana (VIH) y la prevalencia de la farmacorresistencia transmitida en Guatemala. MÉTODOS: Entre octubre del 2010 y marzo del 2011 se incluyeron en el estudio 145 pacientes no tratados anteriormente con antirretrovirales, derivados al Hospital Roosevelt en la Ciudad de Guatemala. Se obtuvieron las secuencias pol a partir del VIH plasmático y se evaluó la farmacorresistencia transmitida con el algoritmo de Stanford y la lista de mutaciones para la vigilancia de la farmacorresistencia transmitida de la Organización Mundial de la Salud (OMS). RESULTADOS: El subtipo B del VIH fue sumamente prevalente en Guatemala (96,6%, 140/145), y se encontró una prevalencia de formas recombinantes BF1 de 2,8% (4/145) y una prevalencia del subtipo C del virus de 0,7% (1/145). La prevalencia de la farmacorresistencia transmitida durante el período de estudio fue de 8,3% (12/145) según el algoritmo de la base de datos de Stanford (puntuación > 15) y la lista de mutaciones para la vigilancia de la farmacorresistencia transmitida de la OMS. En la mayoría de los casos, la farmacorresistencia transmitida se asoció con los inhibidores de la transcriptasa inversa no análogos de nucleósidos (ITINN) (83,3%, 10/12); en la cohorte se observó una baja prevalencia asociada con los inhibidores de la transcriptasa inversa análogos de nucleósidos y con los inhibidores de la proteasa (< 1% para ambas familias de fármacos). Se encontró una baja selección de mutaciones causantes de farmacorresistencia debidas a los antirretrovirales, excepto en las mutaciones asociadas a los ITINN. Las mutaciones importantes relacionadas con los ITINN, como K101E, K103N y E138K, mostraron frecuencias más elevadas que las esperadas en las poblaciones vírgenes de tratamiento antirretroviral. En las personas con un nivel de escolaridad más elevado se encontró un mayor riesgo de farmacorresistencia transmitida (razón de posibilidades 4,14; P = 0,0264). CONCLUSIONES: Este estudio representa uno de los primeros intentos de describir la diversidad del VIH, y la prevalencia de la farmacorresistencia transmitida y sus tendencias en Guatemala. La prevalencia de la farmacorresistencia transmitida en Guatemala presentó un nivel intermedio y en la mayoría de los casos se asoció con los ITINN. Se necesita una vigilancia más intensa y sostenida de la farmacorresistencia transmitida para conocer más exhaustivamente su grado de diseminación y sus tendencias en Guatemala, al igual que para optimizar los resultados del tratamiento antirretroviral en el país.

Antecedentes: As mutações de resistência transmitida do vírus da imunodeficiência humana aos antirretrovirais (TDRM) podem afetar a efetividade da primeira linha dos esquemas empíricos da terapia antirretroviral (TARV). Acredita-se que sua prevalência esteja aumentando no mundo, porém não há resumo claro e conciso da prevalência das TDRM no Brasil e também não se conhece o impacto financeiro que a implantação do teste de genotipagem para detecção de TDRM causaria no sistema de saúde brasileiro. Métodos: Foram realizadas buscas eletrônicas nas bases de dados Medline, Embase, Lilacs e Cochrane CENTRAL (até dezembro de 2015) para identificar estudos observacionais que relatam a prevalência de TDRM do HIV no Brasil e para identificar ensaios clínicos randomizados ou estudos observacionais para avaliar o risco de falha virológica (FV) entre pacientes portadores de HIV virgens de tratamento com e sem TDRM. Foi realizada metanálise de efeitos aleatórios das razões de risco (RR). A heterogeneidade foi avaliada pelo teste de inconsistência (I2) e suas fontes foram investigadas em análise de sensibilidade de subgrupos na meta-análise quando adequado. Para a realização do impacto orçamentário foi desenvolvida uma coorte simulada aberta através de um modelo de Markov. O modelo consistiu de 3 estados: (1) casos incidentes de HIV ( "gerador de paciente" estado); (2) Teste de genotipagem e (estado onde ocorrem os custos) e (3) Saída do modelo (estado absortivo). A duração do ciclo foi de um mês e o horizonte de tempo foi de 5 anos. Não foram aplicados descontos. O número de indivíduos que entram no modelo por ciclo foi projetado a partir de um modelo de regressão derivado de uma série temporal de 10 anos de casos incidentes de HIV. Resultados: Na revisão sistemática da prevalência, 58 estudos atenderam aos critérios de inclusão da revisão sistemática. Cinquenta e sete relataram TDRM para todas as principais classes de drogas e um foi limitado a inibidores da protease (IP). Apenas as mutações atualmente sob vigilância (Stanford, 2015) foram contabilizadas. A meta-análise revelou uma prevalência de TDRM de 8,9% (IC 95% 7,6 a 10,4) (I2 = 10,6%), considerando mutação a qualquer classe de drogas. Os valores para TDRM específicas para NRTI, NNRTI e PI foram de 4,7% (IC 95% 3,7 a 5,9; I2 = 0%); 3,7% (IC 95% 2,9 a 4,6; I2 = 0%) e 2,8% (IC 95% 2,4 a 3,3; I2 = 0%), respectivamente. Entre os subgrupos, a prevalência de TDRM foi menor nos doadores de sangue (5,8%; 95% CI 3,8 a 12,2; I2 = 13%) e maior em homens que fazem sexo com homens (16,9%; IC95% 10,9 a 25,3; I2 = 0% ) e em usuários de drogas injetáveis (13,7%; IC95% 10,3 a 18,1; I2 = 0%). A região com a maior prevalência de TDRM foi a região Sudeste (11,2%; IC95% 9,2-18,6; I2 = 8,6%). No estudo do impacto das mutações de resistência transmitida do HIV aos antirretrovirais na resposta ao primeiro tratamento antirretroviral foram encontrados 28 estudos observacionais (23 de coorte e 5 estudos caso-controle) e nenhum ensaio clínico randomizado relatando taxas de FV entre pacientes portadores de HIV virgens de tratamento com e sem TDRM. O RR de FV para ter qualquer TDRM foi de 1,93 (IC 95% 1,44 a 2,59) em uma meta-análise de 21 estudos de coorte que forneceram informações suficientes (I2 = 82%). Para NRTI, NNRTI e IP, as estimativas de RR em meta-análise foram de 2,58 (IC 95% 1,30 a 5,16); 4,20 (2,21 a 7,96) e 2,92 (1,20 a 7,10), respectivamente. A heterogeneidade diminuiu substancialmente para os subgrupos de classes de drogas (I2 = 65%, 56% e 58%, respectivamente). A avaliação da qualidade metodológica indicou ausência de ajuste abrangente para fatores de confusão em quatro dos 28 estudos e a análise do gráfico de funil indicou uma baixa probabilidade de viés de publicação. As projeções do modelo de regressão linear para incidência anual esperada de HIV entre os anos de 2016 e 2020 variaram de 41022 a 42788 casos, respectivamente. Com 100% incorporação do teste de genótipagem para casos incidentes de HIV desde o início do modelo, o impacto orçamentário acumulado em 5 anos para este cenário foi estimado em R$ 108.244.403,3 (U$ 29.255.244,14). Conclusão: A estimativa pontual para a prevalência geral de TDRM no Brasil é de 8,9%. Isto é comparável às taxas de prevalência observadas em outros países com elevada cobertura da TARV. As evidências disponíveis indicam que as TDRM aumentam o risco de falha virológica entre pacientes portadores de HIV virgens de tratamento. A aplicação universal do teste de genotipagem para casos incidentes de HIV resultaria em um aumento anual aproximado de 22 milhões de reais (5,9 milhões de dólares) para o sistema de saúde público brasileira. Background: HIV transmitted drug resistance mutations (TDRM) could impact the effectiveness of empirical first-line regimens of high active antiretroviral therapy (HAART). Its prevalence is thought to be increasing worldwide, however there is no clear and concise summary of TDRM prevalence in Brazil. Economic evaluations on HIV genotype test for detection of transmitted drug resistance mutations (TDRM) are scarce and the budget impact for the Brazilian public healthcare system has not been estimated. Methods: We did electronic searches on Medline, Embase, Lilacs and Cochrane CENTRAL (up to December 2015) to identify observational studies reporting the prevalence of HIV TDRM in Brazil and to identify randomized clinical trials or observational studies reporting the risk of virologic failure (VF) among treatment naïve HIV patients with and without TDRM. To provide an updated summary prevalence measurement of TDRM among Brazilian treatment naïve adult HIV patients. We performed single-arm random effects meta-analyses of prevalence rates. Ninety-five percent confidence intervals (95% CI) were calculated. Heterogeneity was assessed by the inconsistency test (I2) and its sources were investigated by subgroup and meta-analysis level sensitivity analyses whenever appropriate. To estimate the budget impact of universal HIV genotype test for incident HIV cases in 5 years in Brazil, we developed a Markov model open cohort. The model consisted of three states: (1) HIV incident cases ("patient generator" state); (2) Genotype test and (cost incurring state) and (3) Exit model (absorbing state). Cycle length was one month and time horizon was 5 years. No discounts were applied. The number of individuals entering the model per cycle was projected from a regression model derived from a 10 years period time-series of HIV incident cases. Results: Fifty-eight studies matched criteria to be included in the prevalence systematic review. Fifty-seven reported TDRM for all major drug classes and one was limited to protease inhibitor (PI) TDRM. Only major mutations currently under surveillance (Stanford, 2015) were accounted. Meta-analysis revealed a pooled TDRM prevalence of 8.9% (95% CI 7.6 to 10.4) (I2= 10.6%), considering mutation to any drug class. For NRTI, NNRTI and PI specific TDRM figures were 4.7% (95% CI 3.7 to 5.9) (I2= 0%), 3.7% (95% CI 2.9 to 4.6) (I2= 0%) and 2.8% (95% CI 2.4 to 3.3; I2= 0%), respectively. Among subgroups, TDRM prevalence was lower in blood donors (5.8%; 95% CI 3.8 to 8.8; I2= 3.1%) and higher in men who had sex with men (16.9%; 95% CI 10.9 to 25.3; I2= 0%) and injecting drug users (13.7%; 95% CI 10.3 to 18.1; I2= 0%). The Brazilian territory with the highest TDRM prevalence was the Southeast region (10.9%; 95% CI 8.9 to 13.3; I2= 9.8%). In the study of the impact of HIV TDRM in response to the first antiretroviral treatment we found 28 observational studies (23 cohort, three case-cohort and two case-control studies) and no randomized clinical trial reporting VF rates among treatment naïve HIV patients with and without TDRM. RR of VF for having any TDRM was 1.93 (95% CI 1.44 to 2.59) in a meta-analysis of 21 cohort studies that provided sufficient information (I2=82%). For NRTI, NNRTI and PI, metaanalysis RR estimates were 2.58 (95% CI 1.30 to 5.16), 4.2 (2.21 to 7.96) and 2.92 (1.2 to 7.10), respectively. Heterogeneity decreased substantially for drug class subgroup meta-analyses (I2=65%, 56% and 58%, respectively). Quality assessment indicated absence of extensive adjustment to confounding in four out of 28 studies and funnel plot analysis indicated a low probability of publication bias. Linear model projections for expected annual incidence of HIV between years 2016 and 2020 varied from 41022 to 42788 cases, respectively. With 100% uptake of universal genotype test for incident cases of HIV from model start, annual budget impact estimates were: BRL 21,197,526.48 (USD 5,729,061.21) for 2016; BRL 21,420,723.6 (USD 5,789,384.75) for 2017; BRL 21,650,120.64 (USD 5,851,383.95) for 2018; BRL 21,873,317.76 (USD 5,911,707.50) for 2019 and BRL 22,102,714.8 (USD 5,973,706.70) for 2020. The accumulated 5-years budget impact for this scenario was estimated in BRL 108,244,403.3 (USD 29,255,244.14). Both deterministic and probabilistic sensitivity analyses were performed. Conclusion: The point estimate for the overall prevalence of TDRM in Brazil is 8.9%. This is comparable to prevalence rates observed in other countries with high coverage of HAART. Available evidence indicates that TDRM increases the risk of VF among treatment naïve HIV patients. Universal HIV genotype test for incident HIV cases would result in an approximate annual increase of 22 million BRL (5.9 million USD) for the Brazilian public healthcare system.

Journal Article; Research Support, Non-U.S. Gov't; OBJECTIVES The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade. METHODS The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex). RESULTS No major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K + G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P = 0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P = 0.005). Intermediate- to high-level cross-resistance to twice-daily dolutegravir was predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P = 0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades. CONCLUSIONS No major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K + G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed. Yes

Antiretroviral therapy aims to reduce morbidity and mortality of people with HIV / AIDS, improving the quality and life expectancy. Paradoxically, the irregular treatment may favor the selection of resistant variants, representing a major cause of treatment failure. Such resistant strains can be transmitted to other individuals (transmitted resistance) predisposing to early failure of the inaugural treatment. Resistance tests, particularly genotyping, allow mutation detection in the viral genome. The aim of this study was to characterize the transmitted resistance HIV-1 mutations to antiretroviral drugs in newly diagnosed patients in the Counseling and Testing Center (CTC) in Fortaleza. During the period October 2013 to September 2014, patients with reagent test for HIV were recruited at CTC. Samples for viral load quantitation (Abbott RealTime), CD4 lymphocytes count (BD FACSCalibur) and HIV-1 genotyping (TRUGENE Siemens), were collected. Genetic sequences were aligned by MEGA and BioEdit program. The subtypes of HIV-1 were determined and identified using analysis in REGA HIV subtyping Tool database. The analysis of the antiretroviral resistance mutation was performed using the algorithm of Stanford University (HIVdb Program) and transmitted mutation resistance was identified using the Calibrated Population Resistance (CPR). Biological samples were obtained from 108 patients, among which in 105 was possible to perform the sequencing reaction and evaluation for the presence of mutations to confer antiretroviral drug resistance. The overall prevalence of transmitted resistance in this study was 9.5% (N=10), of those, 2.9% to the NRTI, 5.7% to NNRTI and 1.9% to protease inhibitors. The most prevalent mutation was K103N (25%). The identification of subtypes was performed on 105 samples, being most prevalent subtype B (86.7%), followed by F1 (3.8%) and C (2.8%), as well as recombinant forms (5.7%). It was detected for the first time in Ceará the CRF02_AG (1.9%). BF recombinants were found in 3.8%, F subtype in protease and subtype B in reverse transcriptase, one of those was classified as CRF12_BF. The surveillance of the prevalence of transmitted resistance mutations and the genetic diversity description of the epidemic in the region's population are fundamental to the definition of public health policies. A terapia antirretroviral tem por objetivo diminuir a morbidade e mortalidade das pessoas com HIV/AIDS, melhorando a qualidade e a expectativa de vida. Paradoxalmente, o tratamento irregular pode favorecer a seleção de variantes resistentes, representando uma das principais causas de falha terapêutica. Tais cepas resistentes podem ser transmitidas a outros indivíduos (resistência transmitida), predispondo à falha precoce do tratamento inaugural. Os testes de resistência, principalmente a genotipagem, permitem a detecção de mutações do genoma viral. O objetivo deste estudo foi caracterizar as mutações de resistência transmitida do HIV-1 aos antirretrovirais em pacientes recém-diagnosticados no Centro de Testagem e Aconselhamento (CTA) de Fortaleza. Durante o período de outubro de 2013 a setembro de 2014, foram recrutados pacientes com teste reagente para o HIV realizado no CTA. Foram colhidas amostras para realização de quantificação da carga viral (Abbott RealTime), contagem de linfócitos CD4+ (FACSCalibur BD) e genotipagem HIV-1 (TruGene Siemens). As sequências genéticas foram alinhadas pelo programa MEGA e BioEdit. Os subtipos do vírus HIV-1 foram determinados e identificados empregando análises no banco de dados do REGA HIV Subtyping Tool. A análise das mutações de resistência aos antirretrovirais foi realizada utilizando o algoritmo da Universidade de Stanford (HIVdb Program) e as mutações de resistência transmitida foram identificadas empregando a Calibração de Resistência Populacional. Foram obtidas amostras biológicas de 108 pacientes, sendo que em 105 delas foi possível realizar a reação de sequenciamento e a avaliação quanto à presença de mutações de resistência associadas aos antirretrovirais. A prevalência global de resistência transmitida encontrada neste estudo foi de 9,5% (N=10), sendo 2,9% aos análogos, 5,7% aos não análogos e 1,9% aos inibidores de protease. A mutação mais prevalente foi a K103N (25%). A identificação de subtipos foi realizada em 105 amostras, tendo sido mais prevalente o subtipo B (86,7%), seguido do F1 (3,8%) e C (2,8%), além de formas recombinantes (5,7%). Foi detectado pela primeira vez no Ceará o CRF02_AG (1,9%). Foram encontrados 3,8% de recombinantes BF, sendo subtipo F na protease e subtipo B na transcriptase reversa e um desses foi classificado como CRF12_BF. A vigilância da prevalência das mutações de resistência transmitida e a caracterização da diversidade genética da epidemia na população da região são fundamentais para a definição de políticas públicas de saúde.

OBJECTIVE: To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects. METHODS: In a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%. RESULTS: 7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir. CONCLUSIONS: In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects. Yes OBJETIVO: Para explorar el potencial de profundidad del VIH-1 la secuencia de la adición de información clínica relevante respecto a la población viral secuenciación en gran medida de pre-tratamiento del VIH-1 sujetos infectados. MÉTODOS: En un estudio de prueba de concepto, profundo secuencia se comparó con la secuencia de la población en el VIH-1-las personas infectadas con el anterior, tres clases de fracaso virológico que también desarrollaron falla virológica a profundidad la terapia de rescate, incluyendo, al menos, el darunavir, tipranavir, etravirina o raltegravir. La susceptibilidad del virus se dedujo antes de iniciar el tratamiento de rescate y en el fracaso virológico con profunda genotipos de secuenciación y de la población interpretarse con los algoritmos HIVdb, Rega y la ANRS. El nivel de umbral para la detección de mutantes con profunda secuenciación fue del 1%. Resultados: 7 sujetos con exposición previa a una mediana de 15 antirretrovirales durante una mediana de 13 años fueron incluidos. profunda terapia de rescate incluyó darunavir, tipranavir, etravirina o raltegravir en 4, 2, 2 y 5 sujetos, respectivamente. Auto-reporte de la adherencia al tratamiento fue adecuado en cuatro y parcial en dos, una persona sufrió la interrupción del tratamiento durante el seguimiento. profunda secuenciación detecta todas las mutaciones detectadas por la secuenciación de la población e identificar las mutaciones de resistencia adicional en todos, pero cada uno, sobre todo después del fracaso virológico de profundidad terapia de rescate. Información genotípica adicional condujo a una disminución constante en la susceptibilidad a etravirina predijo, efavirenz, los inhibidores nucleósidos de la transcriptasa inversa e indinavir en 2, 1, 2 y 1 sujeto, respectivamente. profunda secuencia de datos no siempre modificar las predicciones susceptibilidad de la población consigue con la secuencia de darunavir, tipranavir o raltegravir. CONCLUSIONES: En este subgrupo de fuertemente pretratados personas, profunda mejorar la secuencia de la evaluación de la resistencia genotípica a la etravirina, pero no siempre proporcionan información adicional sobre darunavir, tipranavir o susceptibilidad a raltegravir. Estos datos pueden informar el diseño de futuros estudios clínicos frente a los valores de la minoría variantes resistentes a los medicamentos en los sujetos con experiencia en tratamientos.

BACKGROUND: Subtype C is the most prevalent HIV-1 subtype in the world, mainly in countries with the highest HIV prevalence. However, few studies have evaluated the impact of antiretroviral therapy on this subtype. In southern Brazil, the first developing country to offer free and universal treatment, subtypes B and C co-circulate with equal prevalence, allowing for an extensive evaluation of this issue. METHODS AND FINDINGS: Viral RNA of 160 HIV-1+ patients was extracted, and the protease and reverse transcriptase genes were sequenced, subtyped and analyzed for ARV mutations. Sequences were grouped by subtype, and matched to type (PI, NRTI and NNRTI) and time of ARV exposure. Statistical analyses were performed to compare differences in the frequency of ARV-associated mutations. There were no significant differences in time of treatment between subtypes B and C groups, although they showed distinct proportions of resistant strains at different intervals for two of three ARV classes. For PI, 26% of subtype B strains were resistant, compared to only 8% in subtype C (p = 0.0288, Fisher's exact test). For NRTI, 54% of subtype B strains were resistant versus 23% of subtype C (p = 0.0012). Differences were significant from 4 years of exposure, and remained so until the last time point analyzed. The differences observed between both subtypes were independent of time under rebound viremia in cases of virologic failure and of the number of HAART regimens used by treated patients. CONCLUSIONS: Our results pointed out to a lower rate of accumulation of mutations conferring resistance to ARV in subtype C than in subtype B. These findings are of crucial importance for current initiatives of ARV therapy roll-out in developing countries, where subtype is C prevalent.