Resistencia transmitida de VIH-1 en pacientes sin exposición a tratamiento antirretroviral: Guatemala / Transmitted HIV-1 resistance in patients without exposure to antiretroviral treatment: Guatemala / Resistência transmitida ao HIV-1 em pacientes sem exposição ao tratamento antirretroviral: Guatemala

El objetivo del estudio fue describir los niveles de resistencia transmitida de VIH-1 en adultos atendidos en Unidades de Atención Integral de Guatemala. El estudio incluyó registros de 185 pacientes adultos VIH-1 positivo, de reciente diagnóstico sin antecedente de uso de TAR, de noviembre del 2019 a noviembre del 2020. El análisis se realizó en el software DeepChek® v2.0, para la clasificación de la resistencia se siguió el algoritmo de Stanford HIVdb (v9.4 - 07/12/2022). Se encontró 18.4% (IC 95% 13.1 - 24.7%) de resistencia general a alguna familia de ARVs. Se evidenció 15.1% (IC 95% 10.3 - 21.1%) de resistencia individual a la familia de INNTR afectando principalmente a NVP y EFV; 2.2% (IC 95% 0.6 - 5.4%) de resistencia a INTR, mayormente a FTC/3TC; y 2.7% (IC 95% 0.9 - 6.2%) de resistencia intermedia y baja los IP NFV y LPV/r. Tres casos presentaron resistencia múltiple a los INTR + INNTR. Las mutaciones más frecuentemente encontradas fueron K103N (41.2%), M184V/I (8.8%) y M46I (5.9%). La elevada resistencia transmitida del VIH-1 en pacientes atendidos en distintas Unidades de Atención Integral del VIH, demuestra la importancia de analizar periódicamente la tendencia de la resistencia en personas que no han estado expuestas a ARVs, lo cual a su vez es un marcador indirecto de presencia de resistencia adquirida en el país, datos que evidencian la necesidad de acciones e intervenciones prontas y efectivas dado su impacto en la salud pública.

The objective of this study was to describe the levels of transmitted HIV-1 resistance in patients with a recent HIV diagnosis before starting ART, treated in Comprehensive Care Units in Guatemala during the years 2019 and 2020. The study included records of 185 HIV-positive adult patients, recently diagnosed with HIV without a history of ART use. The analysis was carried out in the DeepChek® v2.0 software, the Stanford HIVdb algorithm (v9.4 - 07/12/2022) was followed to classify resistance. 18.4% (95% CI 13.1 - 24.7%) of general resistance to some family of ARVs was found. There was evidence of 15.1% (95% CI 10.3 - 21.1%) of individual resistance to the NNRTI family, mainly affecting NVP and EFV; 2.2% (95% CI 0.6 - 5.4%) resistance to INTR, mostly to FTC/3TC; and 2.7% (95% CI 0.9 - 6.2%) of intermediate and low resistance IP NFV and LPV/r. Three cases presented multiple resistance to NRTIs + NNRTIs. The most frequently found mutations were K103N (41.2%), M184V/I (8.8%) and M46I (5.9%). The high transmitted resistance of HIV-1 in patients treated in different Comprehensive HIV Care Units demonstrates the importance of periodically analyzing the trend of resistance in people who have not been exposed to ARVs, which in turn is an indirect marker. of the presence of acquired resistance in the country, data that demonstrate the need for prompt and effective actions and interventions given its impact on public health.

O objetivo deste estudo foi descrever os níveis de resistência transmitida ao HIV-1 em adultos tratados em Unidades de Cuidados Integrais na Guatemala. O estudo incluiu prontuários de 185 pacientes adultos HIV-1 positivos, recentemente diagnosticados sem histórico de uso de TARV, no período de novembro de 2019 a novembro de 2020. A análise foi realizada no software DeepChek® v2.0, para classificação da resistência, O algoritmo Stanford HIVdb (v9.4 - 07/12/2022) foi seguido. Foi encontrada 18.4% (IC 95% 13.1 - 24.7%) de resistência geral a alguma família de ARVs. Houve evidência de 15.1% (IC 95% 10.3 - 21.1%) de resistência individual à família de NNRTI, afetando principalmente NVP e EFV; 2.2% (IC 95% 0.6 - 5.4%) resistência ao INTR, principalmente ao FTC/3TC; e 2.7% (IC 95% 0.9 - 6.2%) de resistência intermediária e baixa ao IP NFV e LPV/r. Três casos apresentaram resistência múltipla a NRTIs + NNRTIs. As mutações mais frequentemente encontradas foram K103N (41.2%), M184V/I (8.8%) e M46I (5.9%). A elevada resistência transmitida do HIV-1 em pacientes atendidos em diferentes Unidades de Cuidados Integrados ao HIV demonstra a importância de analisar periodicamente a tendência de resistência em pessoas que não foram expostas aos ARVs, o que por sua vez é um marcador indireto da presença de ARVs adquiridos. resistência no país, dados que demonstram a necessidade de ações e intervenções rápidas e eficazes dado o seu impacto na saúde pública.

Prevalencia de resistencia transmitida a drogas antirretrovirales en pacientes con infección por VIH en Chile (2014-2018)

Background: Transmitted drug resistance (TDR) occurs in patients with HIV infection who are not exposed to antiretroviral drugs but who are infected with a virus with mutations associated with resistance. Aim: To determine the prevalence of TDR and characterize HIV reverse transcriptase and protease mutation patterns. Material and Methods: HIV infected antiretroviral treatment-naive patients treated in three centers between 2014 and 2018 were studied. A genotyping study was carried out. The HIVdb Program (Stanford University) and the World Health Organization (WHO) TDR surveillance mutation list were used to register resistance-associated mutations. Results: We enrolled 220 patients aged a median of 29 (interquartile range (IQR) 24-34) years, 99% men. Median CD4 count was 365 cells/μL (IQR 250-499 cells/μL) and median viral load was 39.150 copies/mL (IQR 9,270 −120,000). The overall prevalence of RTD was 10.45% (95% CI 6.7-15.2, N = 23/220). The higher frequency of TDR was against non-nucleoside reverse transcriptase inhibitors, reaching 9.0% (95% CI 5.6-13.6), followed by nucleoside reverse transcriptase inhibitors reaching 1.8% (95% CI 0.49-4.5) and protease inhibitors reaching 0.45% (95% CI 0.01-2.5). The mutations in reverse transcriptase were M41L, L210W, D67N, K70E, M184V, K103N (6.36%, 95% CI 3.5-10.4), G190A, E138A, K101E, and I84V in protease. Conclusions: These results should prompt a change in recommendations for starting antiretoviral therapy, especially in first-line regimens that include non-nucleoside reverse transcriptase inhibitors.

Microbiological study of the subgingival biofilm in HIV+/HAART patients at a specialized dental service / Estudio microbiológico del biofilm subgingival de pacientes VIH+ bajo TARGA en un servicio dental especializado

ABSTRACT The aim of this study was to describe the microbiological profile of HIV patients under highly active antiretroviral treatment (HAART). This crosssectional study comprised 32 HIV patients with periodontal disease (PD) who had been under HAART for more than 6 months. Information about the patients' medical history was obtained from clinical records. Clinical dental examination was performed by a calibrated researcher using standard dental instruments to determine probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP). A total 4,765 periodontal sites were evaluated, 125 of which were also studied microbiologically. Subgingival biofilm samples were obtained using sterile paper points; one set was used for microbiological culture studies and the other for endpoint PCR. Statistical analysis was performed using KruskalWallis and posthoc DunnBonferroni contrast tests. All participants were on HAART at the time of the study, and 90.6% had a viral load below 50 copies/mm3. Prevalence of periodontally active sites was low in the study population. Microbiological studies: Black pigmented anaerobic bacteria and fusiform CFU counts were significantly higher in samples from sites with BOP and PD ≥4mm (p 0.020 and p 0.005, respectively). Molecular Assays: Detection of Porphyromonas gingivalis (p 0.002), Tannerella forsythia (p 0.023) and Treponema denticola (p 0.015) was significantly more frequent at sites with BOP and PD ≥4mm. Conclusions: The patients living with HIV/AIDS under HAART studied here had low prevalence of clinical periodontal disease signs. However, significant detection of P. gingivalis, T. denticola, and T. forsythia in periodontal active sites, and the involvement of these microorganisms as potential HIV reactivators, show the importance of creating awareness among dental health professionals of the need for close dental and periodontal monitoring in HIV patients.

RESUMEN El objetivo de este estudio fue describir el perfil microbiológico del biofilm subgingival de los pacientes con VIH bajo tratamiento antirretroviral de alta actividad (TARGA). El estudio comprendió a 32 pacientes VIH seropositivos con enfermedad periodontal (EP) que se encontraran en tratamiento con TARGA por más de 6 meses. Los antecedentes médicos de los pacientes se obtuvieron de las historias clínicas. El examen clínico instrumental (profun didad de sondaje (PS), nivel de inserción clínico (NIC) y sangrado al sondaje (SS)) fue realizado con instrumental odontológico estándar por un investigador calibrado. De este modo, se evaluaron un total de 4.765 sitios periodontales de los cuales 125 fueron estudiados microbiológicamente. Las muestras de biope lícula subgingival se obtuvieron empleando conos de papel estéril. Las muestras se emplearon en estudios microbiológicos y moleculares por PCR de punto final. El análisis estadístico se realizó según KruskalWallis y pruebas de contrastes posthoc de DunnBonferroni. El 90,6% de la población en estudio presentó carga viral inferior a 50 copias/mm3. La prevalencia de sitios periodontales activos fue baja (1%). Los recuentos de bacterias anaerobias estrictas pigmentadas de negro y fusiformes fueron significativamente más altos en muestras de sitios periodontales con SS positivo y PS ≥4 mm (p 0.020 y p 0.005). La detección molecular de Porphyromonas gingivalis (p 0.002), Tannerella forsythia (p 0.023) y Treponema denticola (p 0.015) fue significativamente mayor en los sitios con SS y PS ≥4mm. La prevalencia del 1% de enfermedad periodontal en el grupo de pacientes estudiados fue menor a la esperada, sin embargo; la detección significativa de P. gingivalis, T. denticola y T. forsythia en sitios periodontales activos y su potencial participación como agentes reactivadores del VIH, nos alerta de la importancia de crear conciencia en los profesionales de la salud (médicos y odontólogos) acerca de la necesidad de un monitoreo minucioso del estado periodontal de pacientes con características semejantes a las descriptas en la muestra poblacional estudiada.

Relevancia clínica de las interacciones medicamentosas en pacientes infectados con el virus de la inmunodeficiencia humana: actualización 2015-2017 / The clinical relevance of drug interactions in patients with human immunodeficiency virus infection: update 2015-2017

Resumen Introducción: La farmacocinética de los anti-retrovirales (ARVs) puede ser modificada por otros medicamentos de uso concomitante. Es oportuno actualizar las interacciones entre nuevos ARVs y fármacos de uso crónico para mantener un éxito terapéutico. Objetivo: Actualizar información sobre interacciones medicamentosas en pacientes con infección por VIH/SIDA en terapia antiretroviral. Método: Revisión estructurada en MEDLINE/ PubMed utilizando los términos Mesh: Anti-retroviral agents and drug interactions or herb-drug interactions or food-drug interactions, entre enero de 2015 y junio de 2017. Fueron seleccionadas publicaciones sobre interacciones medicamentosas en humanos, en inglés o español y con acceso a texto completo. Además, se incluyeron referencias de artículos considerados relevantes. La inclusión de los artículos fue evaluada por tres investigadores independientes y, en caso de requerirlo, por consenso entre ellos. La relevancia clínica se estableció, acorde con la gravedad y probabilidad de ocurrencia de la interacción. Resultados: Se identificaron 466 artículos, se accedió a texto completo a 444. De éstos, 164 aportaron interacciones, lo que permitió identificar un total de 534 parejas de interacciones medicamentosas. Las interacciones que presentaron un mayor riesgo de generar problemas de seguridad y efectividad fueron 308 (57,7%) de nivel 2 y 35 (6,6%) de nivel 1. Conclusiones: Se identifican 534 parejas nuevas de interacciones medicamentosas, de ellas 308 (64,2%) de mayor relevancia clínica.

Background: The pharmacokinetics of anti-retrovirals (ARVs) can be modified by other concomitant medicinal products. It is timely to update the interactions between new ARVs and drugs of chronic use to maintain therapeutic success. Aim: To update information about drug interactions in patients with HIV/AIDS on antiretroviral therapy. Methods: Comprehensive literature review in MEDLINE/PubMed database from January of 2015 to June of 2017, using the Mesh terms: Anti-retroviral agents and drug interactions or herb-drug interactions or food-drug interactions. Publications with drug interactions in humans, in English or Spanish, and with full text were retrieved. Additionally, citation lists from identified articles were reviewed. The study inclusion was assessed by three independent researchers and by consensus among them when was necessary. Clinical relevance of drug interaction was grouped into levels according to seriously and probability of occurrence. Results: 466 articles were identified; full text was accessed in 444. Of these, 164 provided interactions, which allowed the identification of a total of 534 pairs of drug interactions. The interactions that presented a higher risk of generating safety and effectiveness problems were 308 (57.7%) of level 2 and 35 (6.6%) of level 1. Conclusions: We identify 534 new pairs of drug interactions, of which 308 (64.2%) are the most clinically relevant.

Trends and predictors of HIV-1 acquired drug resistance in Minas Gerais, Brazil: 2002-2012

Abstract Several studies show that the prevalence of multidrug-resistant HIV-1 virus is declining over time. A retrospective cohort study was carried out to evaluate the trends of drug resistance in antiretroviral treatment-exposed individuals in a state of a middle-income country, Minas Gerais, southeast region of Brazil. We analyzed 2115 HIV-1 sequences from 2002 up to 2012, from 52 cities of Minas Gerais. The groups were analyzed according to the definitions: "IAS – 3 class mutations", if ≥1 drug resistance mutation from IAS 2015 list (DRM) was present in each class; "No fully susceptible drugs" as the absence of any fully susceptible drug in Stanford algorithm; and "GSS ≥ 2″, when a maximum calculated GSS (genotypic susceptibility score) was ≥2 or ≥3, counting only drugs available in Brazil and USA at given calendar years. Time trends of resistance were analyzed by Cochran–Armitage test. We observed a decrease in the rate resistance mutations for PI, NRTI, "IAS – 3 class mutations", and "No fully susceptible drugs" over these 11 years, from 69.2% to 20.7%, 92.3% to 90.2%, 46.2% to 22.5%, and 12.8% to 5.7%, respectively (p < 0.05). Resistance to NNRTI increased from 74.4% to 81.6%, mainly because of K103N mutation. The GSS score ≥2 increased during the years from 35.9% to 87.3% (p < 0.001). We demonstrate that resistance to PI and to the three main classes simultaneously are declining, although the number of patients on of antiretroviral therapy has doubled in the last ten years in Brazil (125,000 in 2002 to 400,000 in 2014). Broader resistance testing and the availability of more therapeutic options might have influenced this decline. The increase in NNRTI resistance can limit this class as first line treatment in Brazil in the future.

Extensive variation in drug-resistance mutational profile of Brazilian patients failing antiretroviral therapy in five large Brazilian cities

Abstract Background Development of drug-resistance mutations is the main cause of failure in antiretroviral therapy. In Brazil, there is scarce information on resistance pattern for patients failing antiretroviral therapy. Objectives To define the HIV mutational profile associated with drug resistance in Brazilian patients from 5 large cities, after first, second or further failures to antiretroviral therapy. Methods We reviewed genotyping results of 1520 patients failing therapy in five Brazilian cities. Frequency of mutations, mean number of active drugs, viral susceptibility to each antiretrovirals drug, and regional differences were assessed. Results Mean time of antiretrovirals use was 22.7 ± 41.1 months. Mean pre-genotyping viral load was 4.2 ± 0.8 log (2.1 ± 2.0 after switching antiretrovirals). Mean number of remaining active drugs was 9.4, 9.0, and 7.9 after 1st, 2nd, and 3rd failure, respectively. We detected regional variations in drug susceptibility: while BA and RS showed the highest (∼40%) resistance level to ATV/r, FPV/r and LPV/r, in the remaining cities it was around half of this rate. We detected 90% efavirenz/nevirapine resistance in SP, only 45% in RS, and levels between 25% and 30% in the other cities. Regarding NRTI, we found a similar pattern, with RJ presenting the highest, and CE the lowest susceptibility rates for all NRTI. Zidovudine resistance was detected in only 3% of patients in RJ, against 45–65% in the other cities. RJ and RS showed 3% resistance to tenofovir, while in CE it reached 55%. DRV/r (89–97%) and etravirine (61–85%) were the most active drugs, but again, with a wide variation across cities. Conclusions The resistance mutational profile of Brazilian patients failing antiretroviral therapy is quite variable, depending on the city where patients were tested. This variation likely reflects distinctive choice of antiretrovirals drugs to initiate therapy, adherence to specific drugs, or circulating HIV-1 strains. Overall, etravirine and DRV/r remain as the most active drugs.

Seroconversión frente a primovacunación reforzada contra hepatitis B en niños con cáncer / Seroconversion in response to a reinforced primary hepatitis B vaccination in children with cancer

Introducción: La respuesta inmune a los antígenos de las vacunas está disminuida en los niños con cáncer. El objetivo de este estudio fue evaluar la seroconversión frente a vacuna ADN recombinante contra hepatitis B al momento del inicio de la quimioterapia y/o remisión en niños con cáncer. Pacientes y método: Estudio prospectivo, bicéntrico, controlado, no aleatorizado de niños con diagnóstico reciente de cáncer pareados con niños sanos. Los casos fueron vacunados a tiempo 0, 1 y 6 meses, a dosis de 20 y 40 μg si eran < ó > 10 años, respectivamente, con vacuna ADN recombinante contra hepatitis B, en el momento del diagnóstico en el caso de los tumores sólidos y luego de la remisión en el caso de los tumores hematológicos. El grupo control recibió el mismo esquema, con dosis de 10 o 20 μg respectivamente. Se midieron anticuerpos séricos anti-HBs a los 2, 8 y 12 meses posvacunación. Seroconversión se definió como títulos anti-HBs > 10 mUI/ml al octavo mes. Resultados: Un total de 78 niños con cáncer y 25 controles fueron evaluados con títulos anti-HBs al octavo mes. La tasa de seroconversión fue de 26,9%, en niños con cáncer, sin diferencia por edad, género ni tipo de tumor (p = 0,13; 0,29; y 0,44, respectivamente), y de 100% en el grupo control (p < 0,0001, comparado con los niños con cáncer). En el seguimiento a los 12 meses solo el 31,9% de los niños con cáncer presentaba títulos anti-HBs > 10 mUI/ml. Conclusiones: La vacunación contra hepatitis B con vacuna ADN recombinante, con esquema reforzado de 3 dosis, en el momento del inicio de la quimioterapia y/o remisión provee una respuesta inmune insuficiente en la mayoría de los niños con cáncer. En esta población debieran evaluarse vacunas de tercera generación, con adyuvantes más inmunogénicos, esquemas reforzados a los 0, 1, 2 y 6 meses, medición de títulos de anticuerpos al octavo y duodécimo mes, eventual uso de refuerzos y reevaluación de inmunogenicidad si correspondiese.

Introduction: Immune response against vaccine antigens may be impaired in children with cancer. The aim of this study was to evaluate the seroconversion response against hepatitis B vaccination (HBV) at the time of chemotherapy onset and/or remission in children with cancer. Patients and method: Prospective, two-centre, controlled, non-randomised study conducted on children recently diagnosed with cancer, paired with healthy subjects. Cases received HBV at time 0, 1 and 6 months with DNA recombinant HBV at a dose of 20 and 40 μg if < or > than 10 years of age, respectively, at the time of diagnosis for solids tumours and after the remission in case of haematological tumours. Controls received the same schedule, but at of 10 and 20 μg doses, respectively. HBs antibodies were measured in serum samples obtained at 2, 8 and 12 months post-vaccination. Protective titres were defined as > 10 mIU/ml at 8th month of follow up. Results: A total of 78 children with cancer and 25 healthy controls were analysed at month 8th of follow up. Seroconversion rates in the cancer group reached 26.9%, with no differences by age, gender or type of tumour (P = .13, .29, and .44, respectively). Control group seroconversion was 100% at the 8th month, with P < .0001 compared with the cancer group. At month 12 of follow up, just 31.9% of children with cancer achieved anti-HBs antibodies > 10 mIU/ml. Conclusions: Vaccination against hepatitis B with three doses of DNA recombinant vaccine at an increased concentration, administrated at the time of onset of chemotherapy and/or remission provided an insufficient immune response in a majority of children with cancer. More immunogenic vaccines should be evaluated in this special population, such as a third generation, with more immunogenic adjuvants, enhanced schedules at 0, 1, 2, 6 month, evaluation of antibody titres at month 8 and 12 h to evaluate the need for further booster doses.

Validade e fidedignidade de uma escala para avaliar autoeficácia para a atividade física do idoso / Validity and reliability of a scale to assess self-efficacy for physical activity in elderly / Validez y la confianza en la escala para evaluar la autoeficacia de la actividad física de ancianos

Este estudo teve como objetivo analisar a validade fatorial confirmatória e a fidedignidade de uma escala de medida da autoeficácia para atividade física em idosos. Participaram 118 idosos (78% mulheres), com idade entre 60 a 90 anos. Para avaliar a análise fatorial confirmatória utilizou-se o programa Mplus 6.1. A fidedignidade foi testada pela consistência interna e estabilidade temporal. A escala original foi composta por cinco itens com resposta dicotômica (não/sim), de maneira independente para caminhada e atividade física moderada e vigorosa. O item relacionado à confiança em realizar atividade física quando o mesmo está de férias foi excluído. Foram identificados dois construtos denominados "autoeficácia para caminhada" e "autoeficácia para atividade física moderada e vigorosa", com carga fatorial ≥ 0,50. Houve adequados valores de consistência interna, tanto para caminhada (> 0,70) quanto para atividade física moderada e vigorosa (> 0,80) e de estabilidade temporal para todos os itens. Conclui-se que a escala de autoeficácia para atividade física apresenta validade, consistência interna e fidedignidade adequada para avaliar esse construto em idosos brasileiros.

This study aimed to analyze the confirmatory factor validity and reliability of a self-efficacy scale for physical activity in a sample of 118 elderly (78% women) from 60 to 90 years of age. Mplus 6.1 was used to evaluate the confirmatory factor analysis. Reliability was tested by internal consistency and temporal stability. The original scale consisted of five items with dichotomous answers (yes/no), independently for walking and moderate and vigorous physical activity. The analysis excluded the item related to confidence in performing physical activities when on vacation. Two constructs were identified, called "self-efficacy for walking" and "self-efficacy for moderate and vigorous physical activity", with a factor load ≥ 0.50. Internal consistency was adequate both for walking (> 0.70) and moderate and vigorous physical activity (> 0.80), and temporal stability was adequate for all the items. In conclusion, the self-efficacy scale for physical activity showed adequate validity, reliability, and internal consistency for evaluating this construct in elderly Brazilians.

El presente estudio tuvo como objetivo analizar la validez del análisis factorial confirmatorio y la confianza en la escala de medida de autoeficacia en la actividad física de ancianos. Participaron 118 ancianos (78% mujeres), cuya edad fue de 60 a 90 años. Para evaluar el análisis factorial confirmatorio se utilizó el programa Mplus 6.1. La confianza fue comprobada por la consistencia interna y la estabilidad temporal. La escala original estaba compuesta por cinco ítems con respuesta dicotómica (no/sí), de manera independiente para la actividad física moderada y vigorosa. El ítem relacionado con la confianza para realizar la actividad física cuando el sujeto está de vacaciones fue excluido. Fueron identificados dos constructos denominados "autoeficacia para caminata" y "autoeficacia para actividad física moderada y vigorosa", con carga factorial ≥ 0,50. Hubo adecuados valores de consistencia interna, tanto para la caminata (> 0,70), como para la actividad física moderada y vigorosa (> 0,80), y de estabilidad temporal para todos los ítems. Se concluye que la escala de autoeficacia para actividad física presenta validez, consistencia interna y confianza adecuada para evaluar ese constructo en ancianos brasileños.

High frequency of dolutegravir resistance in patients failing a raltegravir-containing salvage regimen

OBJECTIVES: Dolutegravir is a second-generation integrase strand transfer inhibitor (InSTI) that has been recently approved by the FDA to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those already exposed to the first-generation InSTI. Despite having a different mutational profile, some cross-resistance mutations may influence its susceptibility. The aim of this study was to evaluate the impact of a raltegravir-containing salvage regimen on dolutegravir activity. PATIENTS AND METHODS: Blood samples of 92 HIV-infected individuals with virological failure (two or more viral loads >50 copies/mL after 6 months of treatment) using raltegravir with optimized background therapy were sequenced and evaluated according to the Stanford University HIV Drug Resistance Database algorithm. RESULTS: Among the 92 patients analysed, 32 (35%) showed resistance to dolutegravir, in most cases associated with the combination of Q148H/R/K with G140S/A mutations. At genotyping, patients with resistance to dolutegravir had viral load values closer to the highest previously documented viral load. CONCLUSIONS: Changes in viraemia during virological failure may indicate the evolution of raltegravir resistance and may predict the emergence of secondary mutations that are associated with a decrease in dolutegravir susceptibility. Early discontinuation of raltegravir from failing regimens might favour subsequent salvage with dolutegravir, but further studies are necessary to evaluate this issue.

Implementación del estudio farmacogenético de hipersensibilidad al abacavir HLA-B*5701 en Argentina / Implementation of pharmacogenetic study HLA-B*5701 to predict abacavir hipersensitivity in Argentina

El abacavir (ABC) es un antirretroviral inhibidor de la transcriptasa reversa del virus HIV-1 que está fuertemente asociado al desarrollo de reacciones de hipersensibilidad en individuos portadores del alelo HLA-B*5701. Objetivos: determinar la prevalencia del alelo HLA-B*5701 en pacientes HIV-1 positivos y en una población control de Argentina. Materiales y métodos: desde enero de 2012 hasta octubre de 2013 se estudiaron 869 pacientes HIV-1 positivos y 63 individuos no infectados con HIV-1. La detección del alelo HLA-B*5701 se realizó mediante un ensayo in house basado en la técnica de PCR en tiempo real, diseñado en nuestro laboratorio y validado según guías internacionales. Resultados: el primero de enero se implementó el estudio farmacogenético para la detección de hipersensibilidad al ABC en los pacientes incluidos en el Programa VIH/sida de la Dirección de SIDA y ETS, y en los niños infectados con HIV-1 del Hospital Garrahan. Para ello se adoptó un protocolo de envío, recepción y procesado de las muestras, con un informe detallado de los resultados. El alelo HLA-B*5701 se detectó en 42 individuos infectados con HIV-1 y en 3 individuos no infectados. Conclusiones: la prevalencia del alejo HLA-B*5701 en la población de pacientes infectados con HIV-1 y la población control fue la misma (4,8%), lo cual sugiere que la presencia de este alelo no influye en la infección por HIV-1. Esta prevalencia fue similar a la reportada para otras poblaciones de origen caucásico...

Characterization of Gp41 Polymorphisms in the Fusion Peptide Domain and T-20 (Enfuvirtide) Resistance-Associated Regions in Korean HIV-1 Isolates

HIV-1 gp41 is an envelope protein that plays an essential role in virus entry. The mutation of gp41 affects HIV-1 entry and susceptibility to the fusion inhibitor T-20. Therefore, we analyzed the natural polymorphism of gp41 of 163 HIV-1 isolates from T-20-naive Koreans infected with HIV-1. This study of gp41 polymorphisms showed that insertions in the fourth threonine (74.8%) and L7M substitutions (85.3%) were more frequent in the fusion peptide motif in Korean HIV-1 isolates compared with those from other countries. Minor T-20 resistance mutations such as L45M (1.2%), N126K (1.2%), and E137K (6.7%) were detected, but the critical T-20 resistance mutations were not detected in the gp41 HR1 and HR2 regions. In addition, the N42S mutation (12.9%) associated with T-20 hypersusceptibility was detected at a high frequency. These results may serve as useful data for studies considering T-20 for use in the development of a more effective anti-retroviral treatment in Korea.

Effect of Endogenous Bone Marrow Derived Stem Cells Induced by AMD-3100 on Expanded Ischemic Flap

The purpose of this study was to devise an expanded ischemic flap model and to investigate the role of AMD-3100 (Plerixafor, chemokine receptor 4 inhibitor) in this model by confirming its effect on mobilization of stem cells from the bone marrow. Male Sprague-Dawley rats were used as an animal research model. The mobilization of stem cells from the bone marrow was confirmed in the AMD-3100-treated group. The fractions of endothelial progenitor cells (EPC) and the vascular endothelial growth factor receptor (VEGFR) 2+ cells in the peripheral blood were increased in groups treated with AMD-3100. The expression of vascular endothelial growth factor (VEGF) was increased in response to expansion or AMD injection. The expression of stromal cell derived factor (SDF)-1 and VEGFR2 were increased only in unexpanded flap treated with AMD-3100. Treatment with AMD-3100 increased both the number and area of blood vessels. However, there were no statistically significant differences in the survival area or physiologic microcirculation in rats from the other groups. This endogenous neovascularization induced by AMD-3100 may be a result of the increase in both the area and number of vessels, as well as paracrine augmentation of the expression of VEGF and EPCs. However, the presence of a tissue expander under the flap could block the neovascularization between the flap and the recipient regardless of AMD-3100 treatment and expansion.

Péptidos antimicrobianos: un probable arsenal contra la infección por VIH / Antimicrobial peptides: a potential arsenal against HIV infection

La infección por VIH (virus de la inmunodeficiencia humana) en la actualidad es un grave problema de salud pública a nivel mundial, que requiere de nuevas estrategias vacunales para detener su propagación así como para su efectivo tratamiento. Algunos estudios relacionados con la inmunidad innata en contra de VIH, han demostrado que los péptidos antimicrobianos (AMP´s) pueden generar resistencia a las infecciones virales. En la presente revisión, se describen a los péptidos antimicrobianos de humano y su actividad en contra de VIH así como péptidos de otras especies como plantas, anfibios, insectos y varias especies de animales que poseen un potencial terapéutico o profiláctico en la infección por VIH. Se describen brevemente algunos mecanismos mediante los cuales estos péptidos pueden bloquear la replicación e infección por el VIH.

HIV (human immunodeficiency virus) infection is today a very important health issue worldwide, which demands new ways and strategies for its prevention and treatment. Several studies on the innate immunity against HIV infection have shown that antimicrobial peptides are associated with increased resistance to infection. In the present review, we briefly summarize the major characteristics of antimicrobial peptides from human and several species of plants, amphibians, insects and other animal species that have significant potential to be used as therapeutic or prophylactic agents. The mechanisms of infection inhibition and viral replication blockade are also described in the context of the biology of infection.

Human immunodeficiency virus type-2-A milder, kinder virus: An update.

Human immunodeficiency virus type-2 (HIV-2) belongs to the family retroviridae which is phylogenetically clusters with SIV SM from sooty mangabeys. This virus is morphologically similar to human immunodeficiency virus type-1 (HIV-1) but has got only a 40% homology at the nucleotide level. There is a distinct geographical distribution of HIV-2 unlike HIV-1. There are currently eight subtypes/groups identified with subtype/group A responsible for the majority of infections. HIV-2 shows a considerable difference in the course of the disease. Clinical, haematological and immunological evaluation of individuals infected with HIV-2 has shown the virus to be less pathogenic than HIV-1 although the exact mechanism underlying this difference is not well defined. Similar to HIV-1, the HIV-2 isolates also showed distinct replicative and cytopathic characteristics. The transmission rate for HIV-2 compared to HIV-1 is very low both by heterosexual route and mother to child transmission. The clinical signs and symptoms of immunodeficiency associated with HIV-2 are similar to the ones seen among the HIV-1-infected individuals and they can also progress to AIDS. It is naturally resistant to NNRTI and hence the diagnosis become important as it affects the treatment strategy. Similar to HIV-1, HIV-2 strains of infected individuals also show mutations that can cause drug resistance. The current evidence suggests that there is no protective effective for HIV-2 against HIV-1.

Lamivudine-artesunate co-administration affects glucose metabolism in healthy and diseased wistar rats

HIV-Malaria co morbidity frequently requires the co administration of Lamivudine and Artesunate, in Malaria endemic areas where HIV is also a problem. This situation is a frequent occurrence in developing countries of the tropics, like Nigeria where the burden of Malaria and HIV is heavy. The co administration of these drugs may result in interactions with possible physiologic and/or therapeutic consequences. This study investigated the effect of Lamivudine-Artesunate co administration on body weight, relative organ weight and glucose tolerance in healthy and diseased [Plasmodium berghei infected and cyclophosphamide immunosuppressed] wistar rats. Animals received a cumulative 21 day treatment with Lamivudine [20 mg/kg] and/or 7 day Artesunate [10 mg/kg], with healthy or disease controls. Results showed that organ weights and body weights were not affected. Oral glucose was however affected in the combination and Artesunate groups in both disease and healthy rats. The study shows that glucose tolerance is altered with Lamivudine-Artesunate co administration, and may be beneficial, as hypoglycaemia is often a complication of Malaria therapy

Microbicides: a new hope for HIV prevention.

Human immunodeficiency virus (HIV), causative agent of acquired immunodeficiency syndrome (AIDS), is a global health concern. To control its transmission, safe sex has been proposed as one of the strategies. Microbicides- intravaginal/intrarectal topical formulations of anti-HIV agents have also been proposed to prevent HIV transmission. Microbicides would provide protection by directly inactivating HIV or preventing the attachment, entry or replication of HIV in susceptible target cells as well as their dissemination from target cells present in semen or the host cells lining the vaginal/rectal wall to other migratory cells. Microbicides must be safe, effective following vaginal or rectal administration, and should cause minimal or no genital symptoms or inflammations following long-term repeated usage. However, a safe and efficacious anti-HIV microbicide is not yet available despite the fact that more than 60 candidate agents have been identified to have in vitro activity against HIV, several of which have advanced to clinical testing. Nonetheless, proof-of-concept of microbicides has been established based on the results of recent CAPRISA 004 clinical trials. In this article, the trends and challenges in the development of effective and safe microbicides to combat HIV transmission are reviewed.

Microbicides for HIV prevention.

Although the HIV incidence rate has slowed in some countries, HIV remains a serious health challenge, particularly in the developing world. The epidemic is increasingly feminised, with young women at high risk of acquiring the virus. There is thus a clear requirement for acceptable woman-initiated methods of HIV prevention. Foremost among these are vaginally-applied substances known as microbicides; early research into potential microbicides focussed on non-HIV-specific compounds such as surfactants and polyanionic entry inhibitors. However, proof of the microbicide concept as a viable prevention strategy was not provided until the CAPRISA 004 trial of a microbicide containing the HIV-specific antiretroviral tenofovir was completed in mid-2010. Confirmation of the proof of concept provided by CAPRISA 004 by at least two major trials will hopefully lead to licensure of the product by 2018. Parallel studies are planned to ascertain the feasibility of implementation of these products in the public sector with subsequent research focussed on appropriate and acceptable methods of delivery of the active ingredient, and to increase adherence through other delivery systems such as vaginal rings.

Prevalence and patterns of HIV transmitted drug resistance in Guatemala / Prevalencia y patrones de farmacorresistencia transmitida del VIH en Guatemala

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 in-depth 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.

Progress of implementation of the World Health Organization strategy for HIV drug resistance control in Latin America and the Caribbean / Progreso en la aplicación de la estrategia de la Organización Mundialde la Salud para el control de la farmacorresistencia del VIH en América Latina y el Caribe

By the end of 2010, Latin America and the Caribbean (LAC) achieved 63% antiretroviral treatment (ART) coverage. Measures to control HIV drug resistance (HIVDR) at the countrylevel are recommended to maximize the efficacy and sustainability of ART programs. Since 2006, the Pan American Health Organization has supported implementation of the WorldHealth Organization (WHO) strategy for HIVDR prevention and assessment through regional capacity-building activities and direct technical cooperation in 30 LAC countries. By 2010, 85 sites in 19 countries reported early warning indicators, providing information about the extent of potential drivers of drug resistance at the ART site. In 2009, 41.9% of sites did notachieve the WHO target of 100% appropriate first-line prescriptions; 6.3% still experienced high rates (> 20%) of loss to follow-up, and 16.2% had low retention of patients (< 70%) on first-line prescriptions in the first year of treatment. Stock-outs of antiretroviral drugs occurred at 22.7% of sites. Haiti, Guyana, and the Mesoamerican region are planning and implementing WHO HIVDR monitoring surveys or threshold surveys. New HIVDR surveillance tools for concentrated epidemics would promote further scale-up. Extending the WHO HIVDR lab network in Latin America is key to strengthening regional lab capacity to support quality assuredHIVDR surveillance. The WHO HIVDR control strategy is feasible and can be rolled out in LAC. Integrating HIVDR activities in national HIV care and treatment plans is key to ensuring the sustainability of this strategy.

Hacia fines del 2010, América Latina y el Caribe lograron una cobertura de tratamiento antirretroviral de 63%. Se recomienda la ejecución de medidas para controlar la farmacorresistencia del VIH a nivel de país para potenciar al máximo la eficacia y la sostenibilidad de los programas de tratamiento antirretroviral. Desde el 2006, la Organización Panamericana de la Salud ha apoyado la aplicación de la estrategia de la Organización Mundial de la Salud (OMS) para la prevención y la evaluación de la farmacorresistenciadel VIH mediante actividades regionales de formación de capacidad y de cooperación técnica directa en 30 países de América Latina y el Caribe. En 2010, 85 centros en 19 países notificaron indicadores de alerta temprana y suministraron información acerca del alcance de los posibles impulsores de la farmacorresistencia enlos centros de tratamiento antirretroviral. En el 2009, 41,9% de los centros no lograron la meta de la OMS de 100% de prescripción de medicamentos de primera línea apropiados; 6,3% todavía tenían tasas elevadas (> 20%) de pérdida de seguimiento y 16,2% tenían una baja retención de pacientes (< 70%) en tratamiento con antirretrovirales deprimera línea en el primer año de tratamiento. Se registraron desabastecimientos de medicamentos antirretrovirales en 22,7% de los centros. Haiti, Guyana y la zona mesoamericana están planificando y ejecutando estudios de vigilancia de la farmacorresistencia del VIH o estudios del umbral de la OMS. Las nuevas herramientas para la vigilancia de la farmacorresistencia del VIH en las epidemias concentradas permitiránuna mejor vigilancia. La ampliación de la red de laboratorios de farmacorresistenciadel VIH acreditados por la OMS en América Latina es fundamental para el fortalecimientode la capacidad de los laboratorios regionales, a fin de de efectuar una vigilancia de la farmacorresistencia del VIH de calidad garantizada...

HIV transmitted drug resistance in adult and pediatric populations in Panama / Farmacorresistencia transmitida del VIH en poblaciones adultas y pediátricas en Panamá

Objetivo. Investigar la prevalencia de farmacorresistencia transmitida del VIH en adultos en Panamá mediante un estudio del umbral modificado de la Organización Mundial de la Salud (OMS) e investigar las tasas de resistencia inicial en lactantesseropositivos para el VIH en Panamá.Métodos. En el Instituto Conmemorativo Gorgas, en 47 adultos seropositivos al VIH se efectuó la genotipificación de las mutaciones asociadas con la farmacorresistencia transmitida en los genes de la transcriptasa inversa y la proteasa del VIH-1, según las directrices del estudio umbral de la OMS, modificadas para incluir a las personas ≤ 26 años de edad. Las tasas de prevalencia de las mutaciones farmacorresistentes contra tres clases de fármacos antirretroviral —inhibidores de la transcriptasa inversaanálogos de nucleósidos, inhibidores de la transcriptasa inversa no análogos de nucleósidos e inhibidores de la proteasa— se clasificaron en bajas (< 5,0%), moderadas (5,0%–15,0%) o altas (> 15,0%). También se llevó a cabo genotipificación y se calcularonlas tasas de prevalencia de las mutaciones causantes de farmacorresistencia en 25 lactantes.Resultados. En los adultos de Panamá la farmacorresistencia transmitida fue moderada: 6 de 47 adultos seropositivos para el VIH presentaron una o más mutacionesasociadas con farmacorresistencia transmitida. Las mutaciones farmacorresitentes de transmisión horizontal fueron moderadas para los inhibidores de la transcriptasainversa análogos de nucleósidos y los inhibidores de la transcriptasa inversa no análogos de nucleósidos, y bajas para los inhibidores de la proteasa. En Panamá la transmisiónvertical del VIH ha disminuido en el período 2002–2007, pero la prevalenciade la farmacorresistencia del VIH transmitida por vía vertical es moderada (12,0%) y está surgiendo como un problema debido a la cobertura antirretroviral incompletadurante el embarazo...

Objective. To investigate the prevalence of transmitted drug-resistant HIV among adults in Panama by using a modified World Health Organization Threshold Survey (WHO-TS) and to investigate rates of initial resistance among HIV-positive infants in Panama.Methods. At the Gorgas Memorial Institute, 47 HIV-positive adults were genotyped for mutations associated with transmitted drug resistance (TDR) in the reverse transcriptase andprotease genes of HIV-1, according to WHO-TS guidelines, modified to include patients ≤ 26 years old. Prevalence rates for drug-resistance mutations against three classes of antiretroviraldrugs—nucleoside analog reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors—were calculated as low (< 5.0%), moderate (5.0%–15.0%), and high (> 15.0%). Twenty-five infant patients were also genotyped and prevalence rates for drug-resistance mutations were calculated. Results. TDR among Panamanian adults was moderate: 6 of 47 HIV-positive adultsshowed one or more mutations associated with TDR. Horizontal TDR mutations were moderate for NRTIs and NNRTIs and low for protease inhibitors. Vertical transmission of HIV inPanama has decreased for 2002–2007, but vertical HIV TDR prevalence is moderate (12.0%) and is emerging as a problem due to incomplete antiretroviral coverage in pregnancy. Conclusions. The prevalence of HIV TDR indicated by this study, combined with knownrates of HIV infection in Panama, suggests more extensive surveys are needed to identify risk factors associated with transmission of HIV drug resistance. Specific WHO-TS guidelines for monitoring vertical transmission of drug-resistant HIV should be established.