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.

Transmitted drug resistance in patients with acute/recent HIV infection in Brazil

Abstract Introduction: The widespread use of antiretroviral therapy increased the transmission of antiretroviral resistant HIV strains. Antiretroviral therapy initiation during acute/recent HIV infection limits HIV reservoirs and improves immune response in HIV infected individuals. Transmitted drug resistance may jeopardize the early goals of early antiretroviral treatment among acute/recent HIV infected patients. Methods: Patients with acute/recent HIV infection who underwent resistance test before antiretroviral treatment initiation were included in this analysis. HIV-1 sequences were obtained using an in house protease/reverse transcriptase genotyping assay. Transmitted drug resistance was identified according to the Stanford HIV Database for Transmitted Drug Resistance Mutations, based on WHO 2009 surveillance list, and HIV-1 subtyping according to Rega HIV-1 subtyping tool. Comparison between patients with and without transmitted drug resistance was made using Kruskal-Wallis and Chi-square tests. Results: Forty-three patients were included, 13 with acute HIV infection and 30 with recent HIV infection. The overall transmitted drug resistance prevalence was 16.3% (95% confidence interval [CI]: 8.1-30.0%). The highest prevalence of resistance (11.6%, 95% CI: 8.1-24.5) was against non-nucleoside reverse transcriptase inhibitors, and K103N was the most frequently identified mutation. Conclusions: The high prevalence of nonnucleoside reverse transcriptase inhibitors resistance indicates that efavirenz-based regimen without prior resistance testing is not ideal for acutely/recently HIV-infected individuals in our setting. In this context, the recent proposal of including integrase inhibitors as a first line regimen in Brazil could be an advantage for the treatment of newly HIV infected individuals. However, it also poses a new challenge, since integrase resistance test is not routinely performed for antiretroviral naive individuals. Further studies on transmitted drug resistance among acutely/recently HIV-infected are needed to inform the predictors of transmitted resistance and the antiretroviral therapy outcomes among these population.

Síndrome de Cushing iatrogénico por corticoides inhalados en paciente VIH / Cushing syndrome in a HIV patient using inhaled steroids: report of one case

We report a 41-year-old man with HIV and a chronic obstructive pulmonary disease, treated for seven months with Fluticasone/Salmeterol and antiretroviral therapy (Lamivudine, Tenofovir, Atazanavir and Ritonavir). While using these medications, the patients developed a Cushing syndrome in a period of five months. After performing laboratory and imaging tests, it was concluded that the most probable cause of the syndrome was the interaction of inhaled steroids with Ritonavir. After discontinuing these medications the syndrome reverted in a period of 8 months.

A reduced grade of liver fibros-steatosis after raltegravir, maraviroc and fosamprenavir in an HIV/HCV co-infected patient with chronic hepatitis, cardiomyopathy, intolerance to nelfinavir and a marked increase of serum creatine phosphokinase levels probably related to integrase inhibitor use / Grado reducido de fibroesteatosis tras la administración de raltegravir, maraviroc y fosamprenavir en un paciente co-infectado de VIH/VHC con hepatitis crónica, cardiomiopatía, intolerancia al nelfinavir y un aumento pronunciado de los niveles de creatina fosfoquinasa sérica probablemente debido al uso del inhibidor de la integrasa

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir, maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

El uso de nuevos medicamentos antiretrovirales para la infección por VIH es particularmente importante en los pacientes con intolerancia o resistencia a otros agentes antiretrovirales. Raltegravir (RTV) y maraviroc (MRV) representan nuevos e importantes recursos en las terapias de salvamento. Un grado reducido de fibroesteatosis hepática después de una combinación de raltegravir y maraviroc (terapia de segunda línea) no ha sido estudiado, y el mecanismo por el cual estas nuevas clases de droga indujeron una marcada reducción de grado de las enfermedades hepáticas se desconoce hasta el momento. Como parte de la realización en curso de un estudio observacional multicentro acerca del uso de nuevos inhibidores antiretrovirales en pacientes de VIH altamente experimentados en el tratamiento, en el presente reporte de caso se evalúa la correlación entre un "régimen terapéutico corto" (raltegravir, maraviroc y fosamprenavir) y las enfermedades del hígado. El objetivo de este reporte es describir el uso de un régimen de tres medicamentos - basado en dos agentes antiretrovirales de nuevo tipo (raltegravir y maraviroc) además del fosamprenavir inhibidor de la proteasa - en un paciente de VIH experimentado. El paciente también sufre de hepatitis C evolutiva, progresiva, crónica, complicada por fibrosis hepática. Durante el tratamiento, se produjo un aumento extraordinario del nivel de creatina quinasa sérica, el cual probablemente esta relacionado con la administración del inhibidor de la integrasa. Actualmente no hay información disponible con respecto a esta correlación.

Evaluation of inadequate anti-retroviral treatment in patients with HIV/AIDS / Avaliação do uso inadequado de antirretrovirais no tratamento de pacientes com HIV/AIDS

INTRODUCTION: Since the emergence of antiretroviral therapy, the survival of patients infected with human immunodeficiency virus has increased. Non-adherence to this therapy is directly related to treatment failure, which allows the emergence of resistant viral strains. METHODS: A retrospective descriptive study of the antiretroviral dispensing records of 229 patients from the Center for Health Care, University Hospital, Federal University of Juiz de Fora, Brazil, was conducted between January and December 2009. RESULTS: The study aimed to evaluate patient compliance and determine if there was an association between non-adherence and the therapy. Among these patients, 63.8% were men with an average age of 44.0 ± 9.9 years. The most used treatment was a combination of 2 nucleoside reverse transcriptase inhibitors with 1 non-nucleoside reverse transcriptase inhibitor (55.5%) or with 2 protease inhibitors (28.8%). It was found that patients taking lopinavir/ritonavir with zidovudine and lamivudine had a greater frequency of inadequate treatment than those taking atazanavir with zidovudine and lamivudine (85% and 83.3%, respectively). Moreover, when the combination of zidovudine/ lamivudine was used, the patients were less compliant (χ2 = 4.468, 1 degree of freedom, p = 0.035). CONCLUSIONS: The majority of patients failed to correctly adhere to their treatment; therefore, it is necessary to implement strategies that lead to improved compliance, thus ensuring therapeutic efficacy and increased patient survival.

INTRODUÇÃO: A partir do surgimento da terapia antirretroviral, o paciente soropositivo teve sua sobrevida aumentada. A não adesão a essa terapia está relacionada diretamente à falência terapêutica, a qual propicia o aparecimento de cepas virais mais resistentes. MÉTODOS: Foi realizado um estudo retrospectivo e descritivo dos registros de dispensação de antirretrovirais de 229 pacientes do Centro de Atenção à Saúde do Hospital Universitário da Universidade Federal de Juiz de Fora, no período de janeiro a dezembro de 2009. RESULTADOS: Tal estudo teve por objetivo avaliar a adesão do paciente ao tratamento e se houve associação entre a não adesão e a terapêutica. Desses pacientes, 63,8% eram do sexo masculino e apresentavam idade média de 44,0 ± 9,9 anos. Foram realizados 28 esquemas terapêuticos diferentes. Dentre esses, os mais utilizados foram aqueles que combinavam 2 inibidores da transcriptase reversa análogos de nucleosídeos/nucleotídeos com 1 inibidor da transcriptase reversa não análogo de nucleosídeo (55,5%) ou com 2 inibidores de protease (28,8%). Foi verificado que os pacientes em uso de lopinavir/ritonavir ou atazanavir associados à zidovudina e lamivudina apresentaram maiores frequências de tratamento considerado inadequado (85% e 83,3%, respectivamente). Além disso, quando a combinação zidovudina/lamivudina esteve presente no esquema medicamentoso, os pacientes aderiram menos ao tratamento (χ2 = 4,468; grau de liberdade = 1; p = 0,035). CONCLUSÕES: A maioria dos pacientes realizava tratamento considerado inadequado. Portanto, é necessário implementar estratégias que conduzam à melhoria da adesão ao tratamento, a fim de garantir eficácia terapêutica e aumento da sobrevida do paciente.

Prevalence of discordant immunologic and virologic responses in patients with AIDS under antiretroviral therapy in a specialized care center in Brazil / Prevalência da resposta imunológica e virológica discordante em pacientes com AIDS sob terapêutica antirretroviral em ambulatório de centro de cuidados especializados no Brasil

Some patients under antiretroviral therapy (ART) do not reach immune recovery when the viral load becomes undetectable. This is called discordant immunologic and virologic responses. Its prevalence varies between 8 percent and 24 percent. This study describes its prevalence and the characteristics of the affected subjects in the outpatient clinic of a Brazilian specialized-care center. Of 934 patients on ART, 536 had undetectable viral loads. Prevalence was 51/536 or 9 percent (95 percent confidence interval: 6.6 percent to 11.4 percent). Median age at the beginning of ART was 37 years (interquartile range - IQR: 31 to 45). Male gender and mixed race predominated (76.5 percent and 47.1 percent respectively). AIDS-defining illnesses were absent at the beginning of ART in 60.8 percent. Fifty-one percent were taking protease inhibitors, 43.2 percent Efavirenz and 5.8 percent both. Median time on ART was 36 months (IQR: 17-81 months). Irregular treatment was recorded for 21.6 percent. ART had been modified for 63 percent prior to the study, and 15.7 percent had used monotherapy or double therapy. Median CD4 count was 255 cells/mm³ (IQR: 200-284). Median viral load before ART was 4.7 log10 copies/mL (IQR: 4.5-5.2). Discordant responders were not different from AIDS patients in general, but there was a high frequency of multiple schedules of treatment.

Alguns pacientes sob terapêutica antirretroviral (TARV) não obtêm recuperação imune quando a carga viral se torna indetectável. Isto é chamado resposta imunológica e virológica discordante. A prevalência varia entre 8 por cento e 24 por cento. Este estudo descreve sua prevalência e características dos afetados em ambulatório de um centro de cuidados especializados brasileiro. De 934 pacientes sob TARV, 536 tinham carga viral indetectável. A prevalência foi 51/536, ou 9 por cento (Intervalo de Confiança de 95 por cento de 6,6 por cento a 11,4 por cento). Idade mediana no início da TARV foi 37 anos (distância interquartílica - DQ: 31 a 45). Gênero masculino e cor parda predominaram (76,5 por cento e 47,1 por cento, respectivamente). Doenças definidoras de Aids estavam ausentes no início da TARV em 60,8 por cento. Cinquenta e um por cento recebiam inibidores da Protease, 43,2 por cento Efavirenz e 5,8 por cento ambos. Tempo mediano de TARV foi 36 meses (DQ: 17-81). Tratamento irregular foi registrado em 21,6 por cento. TARV havia sido anteriormente modificado em 63 por cento e 15,7 por cento haviam usado mono ou dupla terapêutica. A contagem mediana de CD4 foi 255 células/mm³ (DQ: 200-284). O logaritmo mediano da carga viral antes do TARV foi 4,7 (DQ: 4,5-5,2). Aqueles com resposta discordante não eram diferentes dos pacientes com AIDS em geral, mas houve alta frequência de múltiplos esquemas terapêuticos.

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.

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.

Prevalence and factors associated with darunavir resistance mutations in multi-experienced HIV-1-infected patients failing other protease inhibitors in a referral teaching center in Brazil

Information about resistance profile of darunavir (DRV) is scarce in Brazil. Our objectives were to estimate the prevalence of DRV resistance mutations in patients failing protease inhibitors (PI) and to identify factors associated with having more DRV resistance mutations. All HIV-infected patients failing PI-based regimens with genotyping performed between 2007 and 2008 in a referral teaching center in São Paulo, Brazil, were included. DRV-specific resistance mutations listed by December 2008 IAS-USA panel update were considered. Two Poisson regression models were constructed to assess factors related to the presence of more DRV resistance mutations. A total of 171 HIV-infected patients with available genotyping were included. The number of patients with lopinavir, saquinavir, and amprenavir used in previous regimen were 130 (76 percent), 83 (49 percent), and 35 (20 percent), respectively. The prevalence of major DRV resistance mutations was 50V: 5 percent; 54M: 1 percent; 76V: 4 percent; 84V: 15 percent. For minor mutations, the rates were 11I: 3 percent; 32I: 7 percent; 33F: 23 percent; 47V: 6 percent; 54L: 6 percent; 74P: 3 percent; 89V: 6 percent. Only 11 (6 percent) of the genotypes had > 3 DRV resistance mutations. In the clinical model, time of HIV infection of > 10 years and use of amprenavir were independently associated with having more DRV resistance mutations. In the genotyping-based model, only total number of PI resistance mutations was associated with our outcome. In conclusion, the prevalence of DRV mutations was low. Time of HIV infection, use of amprenavir and total number of PI resistance mutations were associated with having more DRV mutations.

Nutritional assessment and lipid profile in HIV-infected children and adolescents treated with highly active antiretroviral therapy / Avaliação nutricional e do perfil lipídico em crianças e adolescentes infectadas pelo HIV tratadas com terapia antirretroviral de alta potência

INTRODUCTION: HIV-infected children and adolescents treated with highly active antiretroviral therapy (HAART) regimens that include a protease inhibitor (PI) can show significant improvements in clinical outcomes, nutritional status and quality of life. The study aimed to report nutritional and metabolic alterations for pediatric patients continuously exposed to HAART and for healthy controls for up to 1 year. METHODS: Clinical, anthropometric, lipid profile and food intake data were collected prospectively over approximately 12-months for each patient. RESULTS: Fifty-one individuals were studied, of these, 16 were healthy. After 12 months follow-up, HIV-positive individuals remained below the healthy control group parameters. No change was observed concerning food intake. Triglyceride serum levels were higher in patients using protease inhibitor at the onset of the study [PI groups: 114 (43 - 336), and 136 (63 - 271) versus control group: 54.5 (20 - 162); p = 0.003], but after twelve months follow-up, only the group using protease inhibitor for up to two months presented higher values [140 (73 - 273) versus 67.5 (33 - 117); p = 0.004]. HDL-cholesterol was lower in HIV-positive individuals [HIV-positive groups: 36 (27 - 58) and 36 (23 - 43); control 49.5 (34 - 69); p = 0.004]. CONCLUSIONS: HIV-infected children and adolescents treated with highly active antiretroviral therapy showed compromised nutritional parameters compared to a paired healthy control group. Individuals using protease inhibitor presented worse triglyceride serum levels compared to their healthy counterparts.

INTRODUÇÃO: Crianças e adolescentes infectadas pelo HIV e tratadas com terapia antirretroviral de alta potência (TAAP), que inclui inibidor de protease (IP) podem apresentar significante melhora clínica no estado nutricional e na qualidade de vida. O objetivo é relatar as alterações nutricionais e metabólicas em pacientes pediátricos expostos a TAAP e controles saudáveis durante 1 ano. MÉTODOS: O perfil clínico, antropométrico e lipídico, bem como dados da ingestão alimentar foram coletados prospectivamente durante aproximadamente 12 meses. RESULTADOS: Cinquenta e um indivíduos foram estudados. Dezesseis eram saudáveis. Após 12 meses de acompanhamento, indivíduos HIV-positivo permaneceram abaixo dos parâmetros do grupo controle saudável. Nenhuma mudança foi observada em relação à ingestão alimentar. Níveis séricos de triglicerídeos foram maiores em pacientes usando inibidor de protease no começo do estudo [IP grupo: 114 (43 - 336), e 136 (63 - 271) versus grupo controle: 54.5 (20 - 162); p = 0.003], porém após doze meses de acompanhamento, apenas o grupo que recebeu inibidor de protease por não mais do que dois meses apresentou maiores valores [140 (73 - 273) versus 67.5 (33 - 117); p = 0.004]. HDL-colesterol foi menor nos indivíduos HIV-positivos [grupo HIV-positivo: 36 (27 - 58) e 36 (23 - 43); controle 49.5 (34 - 69); p=0.004]. CONCLUSÕES: Crianças e adolescentes infectadas pelo HIV e tratadas com terapia antirretroviral de alta potência tiveram seus parâmetros nutricionais comprometidos quando comparados com o pareado grupo controle. Indivíduos usando inibidor de protease apresentaram piores níveis séricos de triglicerídeos quando comparados com os saudáveis.

Comparison of levels of antiretroviral drugs with efficacy in children with HIV infection.

Objective. To determine the prevelance of low and high antiretroviral (ARV) plasma levels and to analyze correlation between ARV concentrations and the appearance of therapeutic failure and toxicity. Methods. The authors present here a study evaluating antiretroviral plasma concentrations in HIV infected children on nonnucleoside reverse transcriptase inhibitors and protease inhibitors based therapy. The authors carried out a multicentre, crosssectional study, including HIV-infected children from five large Hospitals in Madrid, Spain. Clinical, haematological, biochemical and immuno-virological parameters were assessed. Antiretroviral plasma trough levels were performed using a validated high performance liquid chromatography method. Results. Between April 2006 and April 2008, 129 children were enrolled in the present study, with median treatment duration of 39.2 months. 25.5% of the non-nucleoside reverse transcriptase inhibitors levels were low and 17.6%, high. 27.9% percent of the protease inhibitors levels were low and 12.5%, high. A correlation was found among adequate or high levels of antiretrovirals and normal CD4 percentage and low viral load. Lopinavir/ritonavir plasma levels were correlated with an increase in lipodystrophy. Patients with Tanner stage 1 presented the lowest ARV plasma levels. Full adherence was reported for all the participants by a questionnaire. Conclusion. Many HIV-infected children show ARV plasma levels out of the therapeutic range which demands a child-adjusted approach. However, larger studies are urgently needed in pediatric populations to define optimal reference values.

Estudo da reatividade vascular em portadores de HIV com e sem uso de inibidor de protease / Study of vascular reactivity in HIV patients whether or not receiving protease inhibitor

FUNDAMENTO: Considerando o alto número de pacientes infectados por HIV em uso de antirretrovirais, evoluindo com alteração da função endotelial e aterotrombose, levando ao alto custo médico social, é importante identificar mecanismos fisiopatológicos envolvidos com a função endotelial em portadores de HIV, para que, precocemente, possamos intervir e evitar a progressão da doença. OBJETIVO: Avaliar a função endotelial pela vasodilatação endotélio dependente e independente em pacientes HIV positivo e em grupo controle. MÉTODOS: O estudo avaliou 27 pacientes HIV positivo e 16 do grupo controle. A avaliação da função endotelial foi realizada por meio da vasodilatação da artéria braquial endotélio dependente (hiperemia reativa) e independente (nitroglicerina SL). RESULTADOS: Pacientes HIV positivo em uso de inibidor de protease (IP) apresentaram vasodilatação endotélio independente significativamente menor que os subgrupos HIV negativo (p = 0,020) e HIV positivo sem uso de IP (p = 0,034). A variação do diâmetro da artéria braquial durante hiperemia reativa não apresentou significância estatística em qualquer subgrupo. A análise de regressão linear múltipla mostrou que apenas o IP estava associado ao delta relativo da reatividade braquial pelo vasodilatador, nos pacientes HIV positivo, aos 60 e 90 segundos. CONCLUSÃO: Os pacientes HIV positivo em uso de IP apresentam disfunção endotélio independente quando comparados a pacientes HIV positivo que não fazem uso de IP e a um grupo controle.

BACKGROUND: A great number of HIV-infected patients using antiretroviral drugs develop endothelial dysfunction and atherothrombosis, which lead to a high medical and social burden. Thus, it is important to identify pathophysiological mechanisms involved with the endothelial function in these patients, so that early intervention can be made to avoid disease progression. OBJECTIVE: To evaluate endothelial function using endothelium-dependent and independent vasodilation in HIV-positive patients and in a control group. METHODS: A total of 27 HIV-positive patients and 16 controls were evaluated. Endothelium-dependent (reactive hyperemia) and independent (SL nitroglycerine) vasodilation of the brachial artery was used to evaluate the endothelial function. RESULTS: HIV-positive patients receiving protease inhibitors (PI) showed significantly lower endothelium-independent vasodilation than the HIV-negative (p=0.020) and HIV-positive without PI (p=0.034) subgroups. The change in brachial artery diameter during active hyperemia was not statistically significant in any subgroup. Multiple linear regression analysis showed that only PI was associated with the relative delta of brachial reactivity to vasodilator in HIV-positive patients at 60s and 90s. CONCLUSION: HIV-positive patients receiving PI presented endothelium-independent dysfunction when compared to HIV-positive patients not receiving PI and to the control group.

Alterations in lipid transfer to High-Density Lipoprotein (HDL) and activity of paraoxonase-1 in HIV+ patients / Alterações na transferência de lípides para a lipoproteína de alta densidade (HDL) e atividade da paroxonase 1 em pacientes HIV+

HIV+ patients often develop alterations of the plasma lipids that may implicate in development of premature coronary artery disease. High-density lipoprotein (HDL) has an important role in preventing atherogenesis and the aim of this study was to investigate aspects of HDL function in HIV+ patients. HIV+ patients (n = 48) and healthy control subjects (n = 45) of both sexes with similar age were studied. Twenty-five were not being treated with antiretroviral agents, 13 were under reverse transcriptase inhibitor nucleosidic and non-nucleosidic (NRTI+NNRTI) and 10 were under NRTI + protease inhibitors (NRTI+PI) treatment. Paraoxonase 1 (PON1) activity and the transfer of free and esterified cholesterol, tryglicerides and phospholipids from a lipidic nanoemulsion to HDL were analyzed. In comparison with healthy controls, HIV+ patients presented low PON-1 activity and diminished transfer of free cholesterol and tryglicerides. In contrast, phospholipid transfer was increased in those patients, whereas the transfer of cholesteryl esters was unchanged. NRTI+NNRTI increases the transfer of cholesteryl esters and triglycerides but in NRTI+PI there was no difference in respect to non-treated HIV+ patients. HDL from HIV+ patients has smaller antioxidant properties, as shown by lower PON-1 activity, and the transfer of lipids to this lipoprotein fraction is also altered, suggesting that HDL function is defective in those patients.

Pacientes HIV+ freqüentemente desenvolvem alterações no metabolismo de lípides que podem influir no desenvolvimento de doença arterial coronária. A lipoproteína de alta densidade (HDL) tem papel importante na prevenção da aterogênese. Para investigar aspectos funcionais da HDL na doença, foram estudados 48 pacientes HIV+ e 45 indivíduos-controle saudáveis de ambos os sexos, com idade semelhantes. Vinte e cinco pacientes HIV+ não recebiam terapia antirretroviral, 13 estavam sob tratamento com inibidores nucleosídicos de transcriptase reversa e não-nucleosídicos (NRTI+NNRTI) e 10 sob tratamento com NRTI e inibidor de protease (NRTI+PI). Analisou-se a atividade da paroxonase 1 e a transferência de colesterol livre e esterificado, triglicérides e fosfolipídios de uma nanoemulsão lipídica para a HDL. Pacientes HIV+ apresentaram menor atividade da paroxonase 1 e menor transferência de colesterol livre e triglicérides em relação aos indivíduos saudáveis. A transferência de fosfolipídios foi maior nesses pacientes, mas a transferência de éster de colesterol foi similar. NRTI+NNRTI aumenta a transferência de éster de colesterol e triglicérides, mas em NRTI+PI não houve diferença comparando com os pacientes HIV+ não tratados. A HDL de pacientes HIV+ tem propriedades antioxidantes reduzidas, evidenciada pela menor atividade da paraxonase 1, e transferência de lipídios alterada, sugerindo que a HDL apresente função defeituosa nestes pacientes.

Oral candidiasis in HIV+ patients under treatment with protease inhibitors

The purpose of this work was to evaluate the influence of Protease Inhibitors (PI) on the occurrence of oral candidiasis in 111 HIV+ patients under PI therapy (Group A). The controls consisted of 56 patients that were not using PI drugs (Group B) and 26 patients that were not using any drugs for HIV therapy (Group C). The patient's cd4 cell counts were taken in account for the correlations. One hundred and ninety three patients were evaluated. The PI did not affect the prevalence of oral candidiasis (p = 0.158) or the frequency of C. albicans isolates (p = 0.133). Patients with lower cd4 cell counts showed a higher frequency of C. albicans isolates (p = 0.046) and a greater occurrence of oral candidiasis (p = 0.036).

Factors associated with clinical, immunological and virological responses in protease-inhibitor-experienced brazilian children receiving highly active antiretroviral therapy containing Lopinavir-Ritonavir

This study evaluates clinical, virological and immunological responses to antiretroviral (ARV) therapy based on Lopinavir/ritonovir (LPV/r) in previously protease -inhibitor-experienced children. The study included 29 Brazilian children (median age = 5.91 years) who had failed previous ARV therapy and had begun a regimen based on LPV/r. At 12 months follow-up, a good virological response to LPV/r therapy was defined as achieving an undetectable viral load or as a decrease in plasma HIV RNA levels to > 1 log. A good immunological response was defined as an increase in CD4+ cell count from baseline sufficient to attain a better CDC immune stage classification. The number of infectious episodes 12 months before and 12 months after beginning LPV/r was assessed. Sixteen (55.2 percent) and 19 (65.5 percent) of 29 patients exhibited good virological and immunological responses, respectively. Baseline CD4+ values (>500) predicted both virological and immunological responses (p<0.05). Older children were less likely to develop an immunological response (p<0.001) than younger children. Nine children receiving 3 ARV drugs plus LPV/r showed an immunological response (100 percent) compared to 10/20 (50 percent) children receiving 2 drugs plus LPV/r (p=0.01). A lower number (n<5) of infectious episodes was noted after 12 months follow-up in children using the LPV/r regimen (p=0.006). There was a positive correlation between children whose baseline CD4+ values were greater than 500 cells/mm³ and virological responses. Although virological responses to therapy were seen in about half the children (55.2 percent), the use of HAART containing LPV/r provided clinical and immmunological benefits.

Avascular necrosis of the femoral head in HIV infected patients

Avascular necrosis (AVN) of the femoral head is an emerging complication in HIV infected patients. It has been suggested that the increased incidence of AVN in this population may be caused by an increased prevalence of predisposing factors for osteonecrosis, including protease inhibitors, hyperlipidemia, corticosteroid use, alcohol and intravenous drug abuse. The aim of this study was to assess the risk factors for avascular necrosis developing in the femoral head of HIV infected individuals. This study consisted of meta-analysis of the secondary data extracted from current literature. The selected articles allowed two study groups to be drawn up for comparison. Group 1 comprised 324 individuals infected by the HIV virus, who did not present femoral head AVN. Group 2 comprised 32 HIV positive patients, who presented femoral head AVN. The parameters used for analysis were as follows: age, gender, sexual preference, use of intravenous drugs, time of diagnosis, CD4+ cell count, use of antiretroviral agents and duration, serum cholesterol and serum triglycerides. The present study found a statistically significant association between hypertriglyceridemia, hypercholesterolemia, sexual preference and intravenous drug abuse. The authors concluded that femoral head osteonecrosis is associated with hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) and intravenous drug abuse. This study supports the hypothesis that protease inhibitors play a role in the development of osteonecrosis through a tendency to cause hyperlipidemia.

Urinary NO3 excretion and renal failure in indinavir-treated patients

Treatment with indinavir (IDV), a protease inhibitor, is frequently associated with renal abnormalities. We determined the incidence of renal failure (creatinine clearance <80 mL min-1 1.73 (m²)-1) in HIV patients treated with highly active antiretroviral therapy, including IDV, and investigated the possible mechanisms and risk factors of IDV nephrotoxicity. Thirty-six patients receiving IDV were followed for 3 years. All were assessed for age, body weight, duration of infection, duration of IDV treatment, sulfur-derivative use, total cholesterol, triglycerides, magnesium, sodium, potassium, creatinine, and urinalysis. We also determined renal function in terms of creatinine clearance, urine osmolality and fractional excretion of sodium, potassium, and water. Urinary nitrate (NO3) excretion was measured in 18 IDV-treated patients and compared with that of 8 patients treated with efavirenz, a drug without renal side effects. Sterile leukocyturia occurred in 80.5 percent of the IDV-treated patients. Creatinine clearance <80 mL min-1 1.73 (m²)-1 was observed in 22 patients (61 percent) and was associated with low body weight and the use of sulfur-derivatives. These patients also had lower osmolality, lower urine volume and a higher fractional excretion of water compared to the normal renal function group. Urinary NO3 excretion was significantly lower in IDV-treated patients (809 ± 181 æM NO3-/mg creatinine) than in efavirenz-treated patients (2247 ± 648 æM NO3-/mg creatinine, P < 0.01). The lower NO3 excretion suggests that IDV decreases nitric oxide production.

Restauración de la inmunidad innata en pacientes con infección por VIH/SIDA después de inicio de terapia antirretroviral / Innate immunity restoration in patients with HIV/AIDS infection associated with antiretroviral therapy

Background: Highly active antiretroviral therapy (HAART) in HIV/AIDS infection induces an important reduction of the viral load (VL) and an immune system reconstitution. CD4+ T lymphocyte count is the immunological measurement commonly used for the follow up of HIV/AIDS patients. Aim: To study prospectively the restoration of the innate immune system in patients with HIV/AIDS infection during their first year on HAART. Patients and Methods: 25 naive HIV/AIDS patients, from San José Hospital and University of Chile Clinical Hospital, Santiago, Chile, were studied between years 2002-2003. Every 4 months after HAART initiation, CD3+, CD4+, CD8+ T lymphocytes and CD16/56+ natural killer (NK) cells were quantified by flow cytometry. NK cell cytotoxicity was measured using radioactive chrome liberation (Cr51). Tumor necrosis factor alpha (TNF-a) and interleukin-10 (IL-10) were measured in peripheral blood mononuclear cells and viral load was determined using Amplicor HIV-1 from Roche Diagnostics Systems. Results: Thirteen of the 25 patients continued in the study. They were all males, average age 35 years old (23-50). At baseline average CD4+ count was 146 cells/µL (31-362) and average viral load was 82.000 copies/mL (4.000-290.000). A raise in CD3+, CD4+, CD8+, and CD16/56 cells was noted at months 9-12 of therapy. Viral load became undetectable in the same period. NK cell function was decreased at the beginning of the therapy (1-4 months), reaching its highest values at months 9-12. There was no significant change in IL-10. TNF-a increased in six patients during the study. Conclusions: In this group of patients, innate immunity was restored during HAART. These results should be confirmed in studies with a longer follow up period and also measuring cytokines such as MIP-1a, MIP-1ß and RANTES.