Pharmacovigilance of antiretroviral dolutegravir in the state of Paraná

The aim of this study was to investigate adverse reactions to Dolutegravir, a drug recently made available by the Unified Health System (SUS) for treating HIV infections. The frequency, severity and sex distribution of adverse reactions to Dolutegravir were identified over the first 18 months of its availability in users in the state of Paraná. Information was obtained through the pharmacovigilance questionnaire prepared by the Ministry of Health, accessed through the Logistics Control System for Medicines(SICLOM). During the study period, dolutegravirwas dispensed to 9,865 patients in the state. However, 9,207 users (93.3%) answered the pharmacovigilance questionnaire. Among them, 1.75% reported 279 adverse reactions. This population was composed mainly of male people (69.57%), in the ratio of 2.29 men for each woman, white (67.08%), aged between 20 and 29 years (26.71%), single (45.34%) and with education between 8 and 11 years of study (41.61%). Gastrointestinal (36.92%) and nervous system (14.34%) disorders were the most prevalent. 77.78% adverse reactions were considered non-serious by users. It can be concluded that dolutegravirhad a low prevalence of adverse reactions in users in the state of Paraná, demonstrating to be safe for use by the population in therapy against HIV, in accordance with clinical trials.

Development and validation of RP-HPLC method for simultaneous determination of lamivudine, stavudine, and zidovudine in perfusate samples: Application to the Single-Pass Intestinal Perfusion (SPIP) studies

A reversed-phase high performance liquid chromatography (RP-HPLC) method with ultraviolet detection was developed and validated for the simultaneous quantification of antiretroviral drugs lamivudine (3TC), stavudine (d4T), and zidovudine (AZT) in perfusate samples obtained from the Single-Pass Intestinal Perfusion studies. The chromatographic analysis was performed using a Gemini C18 column and didanosine as internal standard (IS). The following parameters were considered for the validation procedure: system suitability, accuracy, precision, linearity and selectivity. The limits of detection were 0.32 µg/mL for 3TC, 0.11 µg/mL for d4T and 0.45 µg/mL for AZT and the limits of quantification were 1.06 µg/mL for 3TC, 0.38 µg/mL for d4T and 1.51 µg/mL for AZT. Repeatability and intermediate precision ranged from 1.05 to 1.31 and 1.50 to 1.87, respectively, and are expressed as percent of relative standard deviation (RSD). Based on these results, the developed and validated RP-HPLC method can be used for simultaneous determination of 3TC, d4T, and AZT in perfusate samples. Furthermore, this method is simple and adequate for measurements of the antiretroviral drugs in the same sample, since those compounds are mostly co-administered. Besides, this work can be used as an initial base for the development of similar methods in the same conditions presented in our study.

Estimativa de adesão ao medicamento antirretroviral coformulado 3 em 1 / Estimation of adhesion to antiretroviral coformulated 3 in 1

INTRODUÇÃO: Com o propósito de estimular a adesão aos antirretrovirais e minimizar os riscos de resistência a estes medicamentos, o Ministério da Saúde (MS) passou a disponibilizar o medicamento 3 em 1, uma coformulação de tenofovir (300 mg), lamivudina (300 mg) e efavirenz (600 mg), o qual inova com uso de um único comprimido diário. OBJETIVO: Estimar a adesão aos medicamentos antirretrovirais da primeira linha de tratamento contra o HIV. MÉTODOS: Verificação da frequência dos retornos mensais de pacientes a um dispensário dos medicamentos antirretrovirais fornecidos pelo MS. RESULTADOS: Os pacientes em tratamento com o medicamento 3 em 1 foram mais assíduos e retornaram com frequência 65% maior ao dispensário. CONCLUSÃO: Com a introdução do 3 em 1 confirma-se que a simplificação de esquemas terapêuticos é uma medida que facilita a adesão ao tratamento. Isso gera a expectativa de manter por mais tempo os indivíduos em uso da primeira linha de tratamento, retardando a necessidade de recorrer a outras linhas terapêuticas mais onerosas, com maior número de medicamentos e riscos associados.

INTRODUCTION: In order to stimulate adherence to antiretrovirals and minimize the risks of viral mutations and resistance to these drugs, the Ministry of Health (MS) started providing the 3-in-1 drug, a co-formulation of tenofovir (300 mg), lamivudine (300 mg) and efavirenz (600 mg), which innovates by the use of a single daily tablet. OBJECTIVE: Estimating the adherence to antiretroviral drugs in the first line of HIV treatment. METHODS: Verification of the frequency of monthly patient returns to a dispensary of antiretroviral drugs provided by MS. RESULTS: Patients treated with the 3-in-1 medication were more assiduous and returned 65% higher at the dispensary. CONCLUSION: The introduction of 3-in-1 confirms that the simplification of therapeutic schemes is a measure that facilitates adherence to treatment. This generates the expectation of keeping individuals in the first line of treatment longer, delaying the need to resort to other more expensive therapeutic lines, with a higher number of drugs and associated risks.

Antiretroviral therapy immunologic non-response in a Brazilian population: association study using pharmaco- and immunogenetic markers

ABSTRACT Background: Antiretroviral therapy (ART) saved millions from HIV-1 infection and AIDS, but some patients do not experience adequate CD4+ T cells gain despite achieving viral suppression. The genetic component of this condition is not yet completely elucidated. Objective: To identify predictive genetic markers of immune response to ART. Methods: Case-control study. Out of 176 HIV-infected patients recruited in the city of Recife, Northeast Brazil, 67 patients with no immunologic response were the cases and the remaining 109 patients who responded were the controls. A set of 94 selected single nucleotide polymorphisms (SNPs) involved in antiretroviral drugs pharmacodynamic pathways and immune system homeostasis were genotyped, while the remaining 48 were ancestry informative markers (AIMs) for controlling for eventual hidden population structure. Results: Male patients were overrepresented in non-responder group (p = 0.01). Non-responders also started with lower absolute CD4+ T cell counts (p < 0.001). We found five SNPs significantly associated with the outcome, being three more frequent in non-responders than responders: rs2243250 (IL4) A allele (p = 0.04), rs1128503 (ABCB1) A allele (p = 0.03) and rs707265 (CYP2B6) A allele (p = 0.02), whereas the other two were less frequent in non-responders: rs2069762 (IL2) C allele (p = 0.004) and rs4646437 (CYP3A4) A allele (p = 0.04). Conclusion: Some significant univariate associations remained independently associated at multivariate survival analysis modeling, such as pre-treatment CD4+ T cells counts, IL2 and ABCB1 genotypes, and use of protease inhibitors, yielding a predictive model for the probability for immune response. More studies are needed to unravel the genetic basis of ART immunological non-response.

Análisis genético de las mutaciones presentes en las poblaciones virales en pacientes con infección por VIH-1 en Ecuador / Genetic analysis of the mutations in HIV-1 infected population in Ecuador

Resumen Introducción Las recomendaciones internacionales de tratamiento anti-retroviral incluyen pruebas de resistencia para orientar el régimen de tratamiento en cada paciente, lo que no está disponible de forma estable en Ecuador. Objetivo Describir las mutaciones que confieren resistencia a anti-retrovirales en una población de pacientes ecuatorianos. Metodología A partir de muestras de plasma de 101 pacientes con VIH-1 con fallo a la terapia anti-retroviral, 15 niños y 86 adultos, se realizó pirosecuenciación con el GS Junior (Roche) y se analizaron las secuencias con el programa DeepChek. Resultados Las mutaciones más frecuentes fueron M184V/I, K101E/P/H, K103N/S, D30N, M46L/I, I54L/M, V82T/F/A/S/L y L90M en adultos, y F77L, K103N/S, M46L/I, V82T/F/A/S/L y L90M en niños. Se encontró una elevada resistencia a los inhibidores de la transcriptasa reversa (TR) no análogos de nucleósidos en poblaciones minoritarias virales de adultos y niños (34,9 y 70%, respectivamente), en los niños, tanto las poblaciones virales mayoritarias como minoritarias, fueron resistente a inhibidores de proteasa (> 45%). Los pacientes que tuvieron un mayor número de esquemas terapéuticos presentaron mayores niveles de resistencia a los anti-retrovirales. La mayoría de las muestras fueron del subtipo B en la región de la TR y proteasa, y CRF25_cpx en integrasa. Conclusiones Se muestran las mutaciones y la resistencia a antiretrovirales en una población de pacientes ecuatorianos con infección por VIH-1, que permitirán realizar un llamado de alerta a las autoridades de salud sobre la necesidad de realizar estudios de resistencia.

Background The international recommendations of antiretroviral treatment include resistance tests to guide the treatment regimen in each patient, which is not available on a regular basis in Ecuador. Aim To describe mutations that confer resistance to antiretrovirals in a population of Ecuadorian patients. Methods Plasma samples from 101 HIV-1 patients with failure to antiretroviral therapy, divided into 15 children and 86 adults, were studied with the GS Junior (Roche) and the sequences were analyzed with the DeepChek program. Results The most frequent mutations were M184V/I, K101E/P/H, K103N/S, D30N, M46L/I, I54L/M, V82T/F/A/S/L and L90M in adults and F77L, K103N/S, M46L/I, V82T/F/A/S/L and L90M in children. High resistance to non-nucleoside reverse transcriptase (RT) inhibitors in minority viral populations of adults and children (34.9% and 70%) was detected; in children both viral populations (majority and minority viral populations) (> 45%) were protease inhibitor resistant. Patients who had a greater number of therapeutic regimens had higher levels of resistance to antiretrovirals. Most of the samples were subtype B in the TR and protease region, and CRF25_cpx in integrase. Conclusions Mutations and resistance to antiretrovirals are shown in a population of Ecuadorian patients with HIV-1. These results will make it possible to issue a warning to health authorities about the need for resistance studies.

Alerte précoce de la pharmacorésistance du VIH au Togo

Introduction. Dans le cadre de l'ambition globale de mettre fin à l'épidémie du VIH, le Togo a débuté en 2016 la stratégie « Tester et traiter » proposée par l'ONUSIDA pour les cibles telles que les femmes enceintes, couples sérodiscordants, enfants, patients coinfectés TB/VIH, populations clés. Ainsi la stratégie nationale prévoit d'atteindre 90% de couverture de traitement antirétroviral (TARV) à l'horizon 2020. Le passage à grande échelle du TARV peut occasionner une augmentation du risque d'émergence des résistances du VIH aux ARV (RDVIH). La résistance pouvant mettre en échec l'impact de l'accélération en cours du Traitement ARV, nous avons évalué au Togo les indicateurs d'alerte précoce de la pharmacorésistance du VIH (IAP). C'est une stratégie reconnue efficiente dans les pays à ressources limitées pour assurer l'efficacité des protocoles antirétroviraux de première ligne moins dispendieux. Méthodologie. Nous avons en juin 2017 suivant les normes de l'OMS mené une étude rétrospective dans 80 sites de TARV représentatifs des 06 régions sanitaires du pays. Les cinq IAP suivants ont été étudiés : IAP1 : Retrait des médicaments ARV dans les délais ; avec comme seuils : Rouge <80% ; Orange 80­90% ; Vert >90%. IAP2 : Rétention sous TARV après 12 mois d'initiation du traitement avec pour seuils : Rouge <75%; Orange 75­85%; Vert >85%. IAP3 : Ruptures de stocks de médicaments avec comme seuils : Rouge <100%; Vert =100% sans rupture de stock en 2016, IAP4: Pratiques de prescription à l'initiation du traitement ARV avec comme seuils: Rouge <100%; Vert =100% de prescription conformes aux directives nationales. IAP5a : Couverture de réalisation des charges virales avec rendu des résultats avec comme seuils : Rouge < 70%, Vert > 70% des patients ayant une charge virale disponible à 12 mois de TARV. IAP5b: suppression de la charge virale à 12 mois avec pour seuils: Rouge <75%, Orange 75-90%, Vert >90% de suppression de charge virale à 12 mois de TARV, Résultats. Seuls 5468 patients (67%) ont retiré leurs médicaments dans les délais. Cependant 91% (3429/3767) des personnes initiées au TARV sont restées sous traitement douze mois après (IAP 2) mais seulement 5,2% (178/3429) des PVVIH dans le besoin ont eu accès à l'examen de la charge virale, (5a). Seuls 13 sites parmi les 36 ayant un score vert à l'IAP2 avaient atteint l'objectif de suppression de la charge virale (IAP 5b.). Seuls 63 sites sur les 80 ont atteint le seuil de l'IAP et 36/80 enquêtés ont pu atteindre l'objectif de l'IAP2. Conclusion. Nos résultats font craindre un risque d'émergence de la pharmaco-résistance du VIH sur le plan national. Les pratiques de dispensation sont conformes aux directives nationales, la rétention sous TARV à 12 mois est excellente, mais le respect des délais de retrait des médicaments ARV et les ruptures de stocks dans l'approvisionnement des ARV, constituent des facteurs majeurs dans plusieurs sites, pouvant permettre l'émergence de la pharmaco-résistance du VIH au Togo. La couverture de l'examen de la charge virale est très faible et nécessite en urgence d'être étendue

Impacto na qualidade de vida em pacientes usuários de medicação retroviral e submetidos à gluteoplastia: estudo de coorte histórica / Gluteal contour restoration in antiretroviral users and its quality-of-life related impacts: a historical cohort study

INTRODUÇÃO: Desde a introdução do tratamento do HIV com uso da terapia antirretroviral altamente ativa, a mortalidade por essa doença foi reduzida drasticamente em todo o mundo. Um dos parefeitos relacionados à utilização desses fármacos é a lipodistrofia glútea. O objetivo deste trabalho é verificar o impacto da correção dessa deformidade na qualidade de vida de pacientes com HIV. MÉTODOS: Foi conduzido um estudo de coorte histórica com 23 pacientes submetidos à gluteoplastia com implante intramuscular, entre janeiro de 2010 e dezembro de 2014, avaliando a qualidade de vida por meio do em Nottingham Health Profile em. As informações foram coletadas de julho a agosto de 2015. A análise estatística foi feita utilizando-se o em Related-Samples McNemar Test em. RESULTADOS: strong Houve diferença significativa entre o pré-operatório e pós-operatório em 19 das 38 perguntas. CONCLUSÃO: É possível afirmar que a reconstrução glútea melhora a qualidade de vida de pacientes HIV positivos acometidos por lipodistrofia glútea relacionada a antirretrovirais.

INTRODUCTION: Since the introduction of highly active antiretroviral therapy for the treatment of human immunodeficiency virus (HIV), disease mortality has been dramatically reduced worldwide. One related side effect from the use of these drugs is gluteal lipodystrophy. The aim of this study is to assess the quality-of-life impact of correcting this deformity in HIV patients. METHODS: A historical cohort study was conducted between January 2010 and December 2014 with 23 patients, assessing the quality of their lives using the Nottingham Health Profile. A statistical analysis was performed using the McNemar test for related samples. RESULTS: There was a significant difference between preoperative and postoperative response in 19 of the 38 questions. CONCLUSION: We may say that gluteal reconstruction plays a role in improving quality of life for HIV patients who have been affected by antiretroviral related gluteal lipodystrophy.

Avaliação dos mecanismos envolvidos na permeabilidade de fármacos antirretrovirais por meio do modelo de perfusão in situ em ratos / Evaluation of mechanisms involved in the permeability of antiretroviral drugs using the intestinal in situ perfusion model in rats

Para medicamentos administrados oralmente, as etapas de liberação do fármaco a partir da forma farmacêutica e sua subsequente absorção constituem importantes processos para que a adequada biodisponibilidade oral ocorra. Deste modo, as características de solubilidade e de permeabilidade são de extrema importância para que mecanismos relacionados à absorção sejam compreendidos no âmbito das propriedades ADME (absorção, distribuição, metabolismo e excreção). Com base nisso, o Sistema de Classificação Biofarmacêutica (SCB) foi proposto como uma ferramenta que permite a classificação de fármacos em quatro classes distintas de acordo com a solubilidade e permeabilidade. De maneira complementar, o Sistema de Classificação Biofarmacêutica de Distribuição de Fármacos (SCBDF) foi proposto levando em consideração a solubilidade e o metabolismo das substâncias, além de considerar o impacto de transportadores presentes nos tecidos biológicas, inclusive no trato gastrintestinal (TGI). Assim, o presente trabalho teve como objetivo avaliar os mecanismos envolvidos na permeabilidade de fármacos antirretrovirais (estavudina, lamivudina e zidovudina) por meio do modelo de perfusão in situ com coleta de sangue mesentérico em ratos, considerando os aspectos relacionados ao efluxo e ao metabolismo pré-sistêmico que ocorrem nos enterócitos. Além disso, estudos in vitro em culturas celulares MDCK e MDCK-MDR1 foram realizados a fim de auxiliar na elucidação dos mecanismos de transporte dos referidos fármacos. Para a realização dos estudos de perfusão in situ, ratos Wistar foram anestesiados e a porção do jejuno foi canulada para permitir a entrada do fármaco solubilizado no interior do intestino, bem como a coleta das amostras de perfusato em intervalos regulares de tempo. A veia mesentérica também foi canulada para viabilizar a obtenção das amostras de sangue durante os experimentos. Para os estudos de efluxo, o verapamil foi adicionado à solução de perfusão como inibidor de Pgp (glicoproteína-P), enquanto que o cetoconazol foi empregado como inibidor de enzimas CYP3A. Em modelo in vitro MDCK e MDCK-MDR1, os experimentos foram conduzidos bidirecionalmente com o uso de GG918 como inibidor de P-gp. Em todos os experimentos realizados, o metoprolol e a ranitidina foram empregados como marcadores de alta e de baixa permeabilidade, respectivamente. Os resultados de permeabilidade mostraram que a estavudina e a zidovudina apresentam características de alta permeabilidade, enquanto a lamivudina apresentou o menor resultado dentre os três fármacos. Os ensaios bidirecionais em MDCK, no entanto, mostraram que os três antirretrovirais apresentam baixos valores de permeabilidade, uma vez que seus resultados foram significativamente menores que o valor encontrado para o metoprolol. Com relação à avaliação do mecanismo de efluxo, tanto a lamivudina quanto a zidovudina apresentaram interações significativas com a P-gp nos dois métodos empregados (perfusão in situ e MDCK-MDR1), uma vez que o aumento nos valores de permeabilidade foi constatado quando o inibidor de P-gp foi empregado. Os estudos de metabolismo intestinal realizados por meio do modelo de perfusão in situ mostraram que nenhum dos fármacos antirretrovirais apresentou interação significativa com as enzimas CYP3A quando o cetoconazol foi empregado como inibidor, uma vez que não foram constatadas mudanças significativas nos valores de permeabilidade. A comparação entre os resultados de permeabilidade efetiva (Pef) e de permeabilidade aparente (Pap), obtidos por meio da quantificação das amostras de perfusato e de plasma, respectivamente, permitiu verificar que as diferenças estatísticas entre estes dois parâmetros podem indicar variados mecanismos de transporte, uma vez que a Pap constata a quantidade da substância que realmente foi capaz de superar as barreiras físicas e bioquímicas presentes na parede do TGI. Logo, a Pap é considerada um parâmetro mais próximo das condições in vivo. Esta diferença foi constatada apenas para a zidovudina nos ensaios de transporte de efluxo, uma vez que o valor médio de Pef não representou a mesma conclusão fornecida pelo valor médio de Pap. Os resultados obtidos permitiram concluir que os fármacos antirretrovirais apresentam permeabilidade de moderada a alta em função do possível envolvimento de carreadores de influxo. Além disso, os três fármacos antirretrovirais interagiram de alguma forma com a P-gp, sendo os resultados referentes à lamivudina e à zidovudina mais significativos. Embora tenha sido constatada o envolvimento da P-gp na permeabilidade da zidovudina, sua elevada fração absorvida indica que a absorção desta substância não é limitada por este mecanismo e que a ação do carreador de efluxo não é clinicamente relevante neste caso. Com relação aos estudos de metabolismo, a presença de enzimas CYP3A nos enterócitos também não representou uma condição desfavorável para a absorção dos antirretrovirais. Assim, a avaliação dos mecanismos no presente trabalho contribuiu para a caracterização biofarmacêutica da estavudina, lamivudina e zidovudina e as metodologias descritas podem ser empregadas nas etapas iniciais de desenvolvimento farmacêutico com o objetivo de assegurar a segurança e a eficácia de medicamentos.

For orally administered pharmaceutical products, the drug release from the dosage form and its absorption are considered important processes for adequate oral bioavailability. Thus, the solubility and permeability characteristics are extremely important for understanding of mechanisms related to the absorption in the scope of the ADME properties (absorption, distribution, metabolism and excretion). Based on that, the Biopharmaceutics Classification System (BCS) was proposed as a tool for classifying drugs into four classes considering their solubility and permeability characteristics. In an additional way, the Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed considering the solubility and metabolism of compounds. Besides, the BDDCS also considers the impact of transporters in biological tissues, such as in the gastrointestinal tract (GIT). Thus, this study aimed to evaluate the mechanisms involved in the permeability of antiretroviral drugs (stavudine, lamivudine and zidovudine) using the intestinal in situ perfusion model with mesenteric blood sampling in rats, considering efflux and intestinal pre-systemic metabolism that occur in the enterocytes. Furthermore, in vitro studies in cell cultures MDCK and MDCK-MDR1 were performed in order to elucidate the transport mechanisms of the drugs. For intestinal in situ perfusion studies, Wistar rats were anesthetized and a portion of jejunum was cannulated to allow the drug entry into the intestine, as well as the perfusate sampling at regular time intervals. The mesenteric vein was also cannulated to allow blood sampling during the experiments. For efflux studies, verapamil was used as P-gp (P-glycoprotein) inhibitor while ketoconazole was used as CYP3A inhibitor. In in vitro model MDCK and MDCK-MDR1, the experiments were performed bidirectionally using GG918 as P-gp inhibitor. For all experiments, metoprolol and ranitidine were used as markers of high and low permeability, respectively. Permeability results showed that stavudine and zidovudine present high permeability characteristics while lamivudine showed the lowest value. However, bidirectional studies in MDCK showed that the antiretroviral drugs present low permeability since their results are far from metoprolol's results. Regarding efflux studies, both lamivudine and zidovudine presented relevant interaction with P-gp in in situ perfusion and MDCK-MDR1 models, since the increase in permeability values was observed when P-gp inhibitor was added. Metabolism studies performed through intestinal in situ perfusion showed that none of antiretroviral drugs interact significantly with CYP3A enzymes, since that no variation in permeability results were noticed. Comparison between effective permeability (Peff) and apparent permeability (Papp), obtained from prefusate and plasma, respectively, allowed to check that statistical differences between these two parameters can indicate different transport mechanisms, since Papp is related to the drug amount that really overcome the physical and biochemical barriers in the gut. Thus, Papp is considered the closest parameter to in vivo condition. This difference was observed for zidovudine in efflux studies, since Peff values does not match with the conclusion provided by the Papp. The results obtained allowed to conclude that the antiretroviral drugs presents moderate to high permeability due to the involvement of influx carriers. Furthermore, the antiretroviral drugs interacted with the P-gp, but lamivudine and zidovudine showed significant results. Although the involvement between zidovudine and P-gp is observed, its high fraction absorbed indicates that the absorption is not limited by efflux transporter, which is not relevant clinically. Regarding 32 metabolism studies, CYP3A enzymes is not considered as a limiting condition for absorption of the antiretroviral drugs. Thus, the evaluation of the mechanisms contributes for biopharmaceutical characterization of stavudine, lamivudine and zidovudine and the methodologies used in this study can be applied in early drug development to ensure adequate safety and efficacy of pharmaceutical products.

Prevalencia de interacciones medicamentosas con fármacos anti-retrovirales en Buenos Aires, Argentina / Prevalence of potential drug-drug interactions involving antiretroviral drugs in Buenos Aires, Argentina

Introduction: Antiretroviral agents (ARVs) have a high potential for drug interactions. However, the prevalence and risk factors for clinically significant drug-drug interactions (CSDDIs) with ARVs from Latin American countries is unknown. Aim: To evaluate the prevalence and risk factors for CSDDIs in HIV outpatients attending at two centers in Buenos Aires, Argentina. Methods: Descriptive cross-sectional study (september to november 2012). HIV-1 infected patients under ARV treatment at the time of the study were randomly assessed for concomitant medication. CSDDIs were screened using the University of Liverpool Drug Interactions Program (www.hiv-druginteractions.org). Results: A total of 217 patients were included. Male sex: 64% (CI 95: 57-70). Median age (IQR): 41 (36-48). Presence of comorbidities: 19%. ARV regimen: NNRTI-based: 48%, PI-based: 50% and NNRTI plus PI: 2%. Median of CD4 T-cell count (IQR): 402 cells/mL (235-588). Viral load < 50 copies/mL: 78%. Overall, 64% (CI 95: 57-70) of patients had > 1 co-medication of whom a 49% had at least one CSDDI. Two patients had a CSDDI between ARVs. The most frequent co-medications observed were antimicrobial (40%), cardiovascular (25%) and gastrointestinal agents (22%). In the multivariate analysis the number of co-medications and use of CNS agents were associated with the presence of CSDDIs. Conclusions: Co-medications and CSDDIs were common in our setting. In this context, training of HIV physicians in drug interactions is of major importance for adequate management of these patients.

Introducción: Los fármacos anti-retrovirales (ARVs) tienen un alto potencial de interaccionar farmacológicamente con otros medicamentos. Sin embargo, los datos sobre la prevalencia y los factores de riesgo para la presencia de interacciones medicamentosas clínicamente significativas (IMCS) con ARVs en países latinoamericanos son limitados. Objetivo: Evaluar la prevalencia y los factores de riesgo para estas IMCS en dos centros de atención ambulatoria en Buenos Aires, Argentina. Métodos: Estudio transversal y descriptivo (septiembre-noviembre de 2012). Se evaluó la presencia de medicación concomitante en pacientes infectados por VIH bajo tratamiento ARV. Para evaluar la presencia de IMCS se utilizó la base de datos de interacciones de la Universidad de Liverpool (www.hiv-druginteractions.org). Resultados: Se incluyeron 217 pacientes. Sexo masculino: 64% (IC 95: 57-70). Mediana de edad (IQR): 41 (36-48). Presencia de co-morbilidades: 19%. Tratamiento ARV basado en INNTI: 48%, basado en IP: 50% y basado en INNTI más IP: 2%. Mediana de linfocitos T-CD4 (IQR): 402 céls/ml (235-588). Carga viral < 50 copias/ml: 78%. El 64% (IC 95: 57-70) de los pacientes tenían > 1 medicación concomitante: antimicrobianos (40%), fármacos cardiovasculares (25%) y gastrointestinales (22%). De los pacientes que presentaban medicación concomitante 68 (49%) tenían > 1 IMCS y sólo tres (2%) presentaban una asociación contraindicada. Además, dos pacientes tenían una IMCS entre ARVs. En el análisis multivariado, el número de medicamentos concomitantes y el uso psicofármacos se asociaron con una mayor chance de presentar IMCS. Conclusiones: La presencia de medicación concomitante e IMCS fue común en nuestra población. En este contexto, la formación de profesionales de la salud en la detección de interacciones medicamentosas es de suma importancia para un manejo adecuado de pacientes con infección por VIH que reciban tratamiento ARV.

Resistencia a fármacos en pacientes en tratamiento antirretroviral, Cali, Colombia, 2008-2010 / HIV drug resistance in ART-experienced patients in Cali, Colombia, 2008-2010

Introducción. En Colombia se ha publicado poco sobre farmacorresistencia del VIH en pacientes que reciben tratamiento antirretroviral. Las guías de VIH de Colombia de 2006, no recomiendan el uso de los estudios de genotipo de resistencia en pacientes nunca expuestos a medicamentos antirretrovirales ni después del primer fracaso terapéutico. Objetivo. Determinar la frecuencia de mutaciones de resistencia y el grado de sensibilidad/resistencia del VIH a los antirretrovirales en pacientes que han recibido tratamiento antirretroviral. Materiales y métodos. Se reclutó una muestra no probabilística de 170 pacientes con infección por VIH que recibían tratamiento antirretroviral, experimentaban fracaso virológico y que tenían estudios de genotipo de resistencia. Se estudió la farmacorresistencia del VIH en dos grupos: estudios de genotipo de resistencia tempranos Vs . tardíos. Resultados. El tipo de resistencia más frecuente en pacientes bajo tratamiento antirretroviral, afectó a los inhibidores no nucleosídicos (76 %). El grupo de estudio tardío tuvo mayor riesgo de resistencia a inhibidores nucleosídicos y a los inhibidores de proteasa, mayor número de mutaciones de resistencia y mayor complejidad de las resistencias, que el grupo de estudio temprano. También, se encontró un alto grado (30 %) de resistencia cruzada a los inhibidores nucleosídicos en el grupo de estudio tardío. Los medicamentos menos afectados fueron tenofovir y darunavir. Conclusiones. Los resultados de este estudio sugieren que practicar estudios de genotipo de resistencia tardíos se asocia con altos niveles de resistencia, lo cual puede restringir el uso de un gran número de antirretrovirales esenciales en esquemas subsiguientes. Es necesario revisar las actuales recomendaciones sobre el uso de dichos exámenes en las guías colombianas de manejo de VIH.

Introduction: Little has been published in Colombia on HIV drug resistance in patients taking antiretroviral treatment (ART). Currently, the Colombian guidelines do not recommend the use of genotypic antiretroviral resistance tests (GART) for treatment-naive patients or for those experiencing a first therapeutic failure. Objective: To determine the frequency of relevant resistance mutations and the degree of susceptibility/ resistance of HIV to antiretroviral drugs (ARVs) in ART-experienced patients. Materials and methods: A non-random sample of 170 ART-experienced HIV patients with virologic failure and who underwent GART was recruited. A study of HIV drug resistance was carried out in two groups of patients: one group that underwent early GART and the other group that received late GART testing. Results: The most frequent type of resistance affected the non-nucleoside class (76%). The late-GART group had higher risk of nucleoside analog and protease inhibitor drug resistance, a higher number of resistance mutations and more complex mutational profiles than the early-GART group. A high cross resistance level (30%) was found in the nucleoside analog class. The least affected medications were tenofovir and darunavir. Conclusions: Our results suggest that performing GART late is associated with levels of ARV resistance that could restrict the use of an important number of essential ARV in subsequent regimens. There is a need to revise the current recommendations to include GART prior to start of treatment and after the first virologic failure.

Perfil del paciente vih/sida en tarv, consulta de vih, hospital Dr. Felipe Guevara Rojas, el tigre anzoateguí / Patient Profile HIV / AIDS on ART, HIV consultation, hospital Dr. Felipe Guevara Rojas: Tiger anzoátegui

Es conocida la importancia de la adherencia antirretroviral. En la región, no hay datos disponibles de las características y adherencia de los pacientes con infección por el VIH con o sin tratamiento antirretroviral. Caracterizar el perfil, adherencia y razones de poco cumplimiento al tratamiento antirretroviral de los pacientes de la consulta del Hospital Dr. Felipe Guevara Rojas, El Tigre, Anzoategui. Cuestionado validado por PNSIDA/ITS del MPPS en el estudio nacional de adherencia antirretroviral (2008). Se entrevistraron pacientes voluntarios, forma anónima, en tratamiento antirretroviral que acudieron a la consulta entre octubre/noviembre 2011. Se realizaron tablas y gráficos. 45/244 (18,4%) del total de pacientes controlados. 51,11% mujeres, mayoría entre 26-35 años (48,89%). 20% aceptó consumir alcohol, menos del 50% en primaria. En el 88,89% la familia conocia diagnóstico. 66,67% cumplía esuemas menores de 2 años, 75,56% un primer esquema. Solo 5% multitratados. Un 28,89% aseguró no tomarse alguna pastilla en última semana (61,54% de 1-2 pastillas). Razones principales: estar ocupado (46,15%) y olvido (38,46%). La adeherencia aproximadas es 71,11%. Debe ser tomado como diagnóstico situacional, con definición de posibles estrategias de intervención. En la región, es el primer estudio en el tema. La medición de la adeherencia es dificil y mantenerla elevada genera el trabajo conjunto de todo el personal de salud involucrado en la atención del paciente.

We know the importance of adherence antiretroviral. In the region, there is no data available on the characteristics and adherence of patients with HIV infection with or without antiretroviral therapy. To characterize the profile, adherence and no treatment compliance reasons to antiretroviral therapy of patients visiting the Hospital Dr. Felipe Guevara Rojas El Tigre, Anzoategui Questionnaire validated by PNSIDA / STI of MPPS in adherence antiretroviral adeherence nationatl study (2008). Volunteer patients were interviewed, anonymously, on antiretroviral therapy who attended the consultation beteen octobrer/november 2011. There were tables and graphs. Sample: 45/244 (18.4%) of all patients monitored. 51.11% females, mostly between 26-35 years (48.89%). 20% admited using alchol, less than 50 % in primary. In 88.89 % family known diagnosis. 66.67% met under 2 schemes, the first scheme 75.56 %. Only 5 % multitreated 28.89 % said not taking a pill in last week (61.54 % of 1-2 tablets. Main reasons: being busy (46.15%) and forgetfulness (38.46%). Adherence is approximately 71.11%. It should be taken as situational analysis, defining possible intervention strategies. In the region, is the first study on the subject. Measuring adherence is difficult and keep it elevated generates all work together health staff involved in patient care.

Incidence of Adverse Drug Reactions in Patients on Antiretroviral Therapy: A study of Pharmaceutical Care in HIV Interventions in Nigeria

Background: Over 415;000 HIV-infected patients are receiving antiretroviral therapy (ART) in Nigeria but studies documenting their adverse reactions are limited. Objectives: This study determined the incidence and type of ADRs of severity grades II to IV in ART patients following pharmaceutical care directed active ADR surveillance program in Nigeria. Methods: This was a longitudinal study. A study-specific pharmaceutical care daily work sheet and national ADR reporting form were used for ADR screening and reporting respectively. Study population included 73;589 ART patients who were screened for ADR from April 2009 to December 2010 in 69 HIV treatment centres. All individual case safety reports (ICSRs) of severity grades II to IV in these patients were collated and analyzed. Chi-square was used to test the association between groups of variables at 95 Confidence Interval. Results: A total of 4600 ICSRs of severity grades II to IV reported were analyzed. Mean age of patients was 35.5(95CI; 35.2-35.9) years; 68.1 were females; and 7002 ADRs were reported; an average of 1.5 ADR perpatient. ADR incidences were 18.2 for d4T/3TC/EFV; 13.9 for d4T/3TC/NVP; and 4.4 for AZT/3TC/NV Pregimens; however overall incidence was 6.3. Major reported ADRs included skin rash (16.5); peripheral neuropathy (12.7); and headache (9.4). ADR occurrence was associated with specific ART regimens; concomitant medicines and age groups (p0.05); unlike gender. Lipodystrophy was associated withd4T/3TC/NVP [OR

Licenciamento compulsório e acesso ao tratamento do HIV/AIDS no Brasil / Compulsory licensing and access to treatment for HIV / AIDS in Brazil

O presente estudo tem por objeto analisar a aplicação da medida de licenciamento compulsório em relação às patentes do medicamento antirretroviral Efavirenz. A pesquisa se apresenta sob caráter descritivo, configurando pesquisa bibliográfica e documental, sendo o meio de investigação o estudo de caso. No decorrer do estudo percebeu-se que o licenciamento compulsório do Efavirenz mostrou-se experiência exitosa, impactando de forma positiva no Programa Nacional de Doenças Sexualmente Transmissíveis e AIDS (PN DST/AIDS), resultando numa economia de mais de cem milhões de dólares com a compra do medicamento nos anos de 2007 a 2011, bem como no aumento do número de pacientes em tratamento com o Efavirenz, que saltou de 75mil em 2007 para 105 mil em 2011. Foram identificadas dificuldades para a implementação da medida, como a falta de capacidade técnica imediata para a produção do medicamento e seu insumo farmacêutico ativo (IFAs), bem como o enfrentamento depressões internacionais de países desenvolvidos. Muito embora a medida represente experiência de sucesso, constatou-se não ter havido qualquer iniciativa governamental de aplicação de licença compulsória a outro medicamento de suma importância para o Sistema Único de Saúde (SUS). Nota-se uma mudança de orientação do Ministério da Saúde quanto às medidas adotadas para promoção do acesso a medicamentos e desenvolvimento do complexo industrial da saúde brasileiro, em que se destaca a emergências das Parcerias para Desenvolvimento Produtivo (PDPs).

Perfil Genotípico de Resistência do HIV em pacientes com falha virológica ao esquema antirretroviral de primeira linha na coorte de pacientes com HIV/AIDS do Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz / Genotypic resistance profile of HIV in patients with virological failure to first-line antiretroviral regimen in a cohort of patients with HIV / AIDS Clinical Research Institute Evandro Chagas-Fiocruz

Introdução: Ao longo dos trinta anos de identificação do HIV como agente etiológico, muitas mudanças ocorreram, principalmente em relação ao tratamento dos pacientes. [...] Objetivos: Descrever o perfil genotípico por ocasião da primeira falha virológica em uso de um esquema inicial de cART; Avaliar o impacto do perfil mutacional no momento da primeira falha no uso potencial da etravirina em esquemas antirretrovirais subsequentes; Descrever o perfil da população baseando-se no escore de mutações da etravirina e analisar os fatores relacionados à redução na sensibilidade a esta droga; Avaliar a prevalência de genotipagens com de vírus selvagem e analisar os fatores associados à sua ocorrência; Descrever os fatores relacionados à mutação K65R na primeira falha à cART. Métodos: Estudo com coleta de dados a partir de prontuários médicos e exames de genotipagem de pacientes com HIV acompanhados no IPEC que tiveram a falha virológica ao esquema antirretroviral inicial no período de 2000 a 2012. [...] Resultados: Foram incluídos 166 pacientes nesse estudo. O subtipo viral predominante foi o B (65,3 por cento). Nos 113 pacientes que usaram esquemas baseados em ITRNN (66,5 por cento), a mutação mais frequente para esta classe foi a 103N. Entre os 17 pacientes que fizeram uso de IP sem booster, as mutações mais frequentes na protease foram a 30N, 32I e 46ILV e entre os 36 pacientes que fizeram uso de IP com booster as mutações mais frequentes na protease foram a 82ATF, 90M e 46ILV...

Introduction: Over thirty years of HIV epidemic, many changes have occurred, especially in term's of patients treatment. [...] Objectives: To describe the genotypic profile at the first virologic failure while using the firstline cART; evaluate the impact of the mutational profile at the time of first failure in the potential subsequent use of etravirine for salvage regimens; describe the profile of the population relying etravirine´s mutations and analyze the factors related to reduced sensitivityto this drug; evaluate the prevalence as well as the associated risk factors of genotyping withthe presence of wild-type virus; describe the factors related to the presence of K65R mutationat the first failure to cART.Methods: The study included data collection from medical records and genotyping of HIV patients followed at IPEC who had presented virologic failure for initial antiretroviral regimenin the period of 2000 to 2012. [...] Results: 166 patients were included in this study.The predominant virus subtype was B (65.3 percent). Among the 113 patients using NNRTI -based regimens, the most frequent mutation to NNRTI was 103N. Among the 17 patients who used an unboosted PI, the most prevalent mutations in protease were 30N, 32I and 46ILV. Among the 36 patients who used boosted PI the most frequent mutations in protease were 82ATF, 90M and 46ILV. The most frequent NRTI mutation into the three groups was 184VI...

Resistencia a los antirretrovirales: Informe preliminar del capítulo de Guatemala, del estudio de epidemiología molecular del VIH en la región de mesoamerica / Antiretroviral resistance: initial report of Guatemala chapter, the study of molecular epidemiology of HIV in the region of Mesoamerica

El uso más extendido de los fármacos antirretrovirales ha traído como consecuencia la transmisión de variantes virales con mutaciones de resistencia que se pueden mantener en individuos sin tratamiento antirretroviral. La frecuencia de estas mutaciones de resistencia transmitida es relativamente alta en países desarrollados, muchas veces con tendencias de aumento. En países en vías de desarrollo, en los que la terapia antirretroviral (ARV) se introdujo posteriormente, las frecuencias de resistencia primaria tienden a ser menores, probablemente porque su uso se encuentra basado en una disponibilidad relativamente limitada...

Descentralización de los tratamientos antirretrovirales en el Hospital de Escuintla / Decentralization of antiretroviral treatment in the Hospital of Escuintla

La pandemia de la infección por VIH es uno de los retos de salud pública nunca afrontados por la humanidad. Una línea de acción es el Tratamiento Antirretroviral (TARV) que puede detener la progresión de la enfermedad y estabilizar al paciente. En Guatemala la administración de antirretrovirales y el seguimiento de los pacientes con TARV en el 2004 estaban centralizados en los Hospitales Roosevelt, San Juan de Dios, Puerto Barrios , Izabal, Coatepeque y Quetzaltenango. Esto dificultaba el seguimiento y la adherencia al tratamiento cuando estos vivían alejados de dichos hospitales...

Impacto económico de la atención del niño expuesto a VIH, con antirretrovirales durante el embarazo, Hospital Roosevelt Guatemala año 2011 / Economic impact of child care exposed to HIV, antiretroviral during pregnancy, Roosevelt Hospital Guatemala 2011

En el 2002 la Clínica de Enfermedades Infecciosas, inició en el departamento de Ginecoobstetricia del Hospital Roosevelt, la atención a madres embarazadas para prevenir la transmisión vertical del VIH, hepatitis B y sífilis, a través del tamizaje universal y seguimiento de los casos detectados. En el año 2006 se inicia la atención a niños expuestos en clínica pediátrica de consulta externa. Atendiendo de esta manera a la madre y el seguimiento de madres VIH positivo y niños expuestos nacidos en el Hospital Roosevelt y casos referidos de otras instituciones, públicas y privadas...

Resistencia primaria del VIH a los antirretrovirales: informe preliminar del capítulo de Guatemala del estudio de epidemiología molecular del VIH en la región Mesoamericana / Primary HIV resistance to antiretroviral drugs: preliminary report of Guatemala chapter of molecular epidemiology study of HIV in Mesoamerica

Métodos: se seleccionaron pacientes adultos con diagnóstico reciente de infección por VIH, o con diagnóstico previo y que no habían iniciado terapia antirretroviral, que fueron enrolados como parte del estudio Epidemiología Molecular y vigilancia de farmacorresistencia del VIH-1 en la Región Mesoamericana, durante los meses de octubre de 2010 y agosto de 2011 en el Hospital Roosevelt, ciudad de Guatemala. La participación fue debidamente informada y voluntaria...

Abandono de tratamiento antirretroviral en pacientes femeninas en edad reproductiva con diagnóstico de virus de inmunodeficiencia humana VIH/ síndrome de inmunodeficiencia adquirida-SIDA- que asisten a la clínica de enfermedades infecciosas del Hospital Roosevelt / Abandonment of antiretroviral treatment in female patients of reproductive age diagnosed with HIV human immunodeficiency virus / acquired immunodeficiency syndrome-AIDS attending the clinic of infectious diseases at Roosevelt Hospital

La presente investigación tuvo como objetivo estudiar el abandono de tratamiento antirretroviral (ARV) en pacientes femeninas en edad reproductiva, consistió en determinar el porcentaje y las causas de abandono de dicho tratamiento en pacientes que asistieron a la Clínica de Enfermedades Infecciosas del Departamento de Medicina Interna del Hospital Roosevelt, durante el período de enero 2005 a diciembre 2009. La investigación fue de tipo descriptivo-retrospectivo, mediante revisión sistemática de 1,000 registros médicos de pacientes a estudio que evidenciaron el inicio de tratamiento antirretroviral y el abandono del mismo por un mínimo de dos meses consecutivos...

El tratamiento antirretroviral puede convertir la infección por VIH en una enfermedad crónica / Advances in antiretroviral therapy may transform HIV infection into a chronic illness

A diferencia de nuestro ensayo clínico de tratamiento antirretroviral (AR) de gran actividad (TARGA) publicado en "Revista Clínica Española", que se llevó a cabo de 1997 a 1999, en el que sólo había 7 AR de dos familias con 2 inhibidores de la proteasa (IP) para el TARGA de la infección por VIH; actualmente tenemos 22 AR con 10 IP (tipranavir y darunavir con mejor perfil de resistencia). Hay nuevas familias: no análogos de los nucleósidos; inhibidores de la fusión (enfurtivide), del CCR5 (maraviroc) y de la integrasa (raltegravir). El tratamiento de los usuarios de drogas por vía parenteral ha cambiado con programas de metadona. La adhesión aumenta con preparados asociados y menor número de comprimidos a dos al día y a uno al día y reduce efectos adversos (lipodistrofia). Respecto de la cohorte de nuestro hospital de 488 pacientes, en el estudio transversal del 2008 (pacientes en seguimiento con TARGA), un 82% tienen carga viral (CV) menor de 50 copias/ml, y otro 14%, menor de 500 copias/ml. Estos resultados contrastan con los de nuestro ensayo clínico (20% con CV menor de 400 copias/ml). Presentan CD4 mayor de 500/ml: 59.4% de los pacientes de la cohorte, CD4 mayor de 200/ml: 93.7% y un 2.8% CD4 menor de 50/ml. Actualmente el objetivo general es disminuir la CV por debajo de 50 copias/ml, avance importante en el tratamiento de la infección por VIH para convertirla en una infección crónica.

In the period 1997 to 1999, our clinical trial of antiretroviral therapy (ART) of high efficacy (HAART), published in «Revista Clínica Española¼, revealed only 7 ART in two families with 2 protease inhibitors (PI) for HAART regimens to treat HIV infection. However, at present we have 22 ART with 10 PI (tipranavir and darunavir with better resistance profile). There are newART families: nonnucleosides, and fusion (enfuvirtide), CCR5 (maraviroc) and integrase (raltegravir) inhibitors.Methadone programs have changed the treatment of the parenteral drug users. Associated pharmaceutical preparations and a small number of tablets, two tablets/day, or one tablet/day, augment adherence and reduce adverse effects (lipodystrophy). Regarding our hospitalcohort of 488 patients, in the 2008 transversal study (patients on HAART), 82% have viral load (VL) less than 50 copies/ml and other 14% of the patients had VL of less than 500 copies/ml. These results do not coincide with those of our clinical trial (20% of patients had VL of less than 400 copies/ml). CD4 counts above 500/ml were present in 59.4% of the patients of the cohort, CD4counts above 200/ml in 93.7%, and only 2.8% of the patients had less than 50 CD4/ml. At present, the generalobjective is to reduce the VL to less than 50 copies/ml; this is an important advance in the treatment of HIV infection and makes it a chronic infection.