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OBJECTIVE: To date, no data exist regarding the prevalence of integrase inhibitor (INSTI) resistance-associated mutations (HIVDRM) in HIV-infected pregnant women (HPW) in Latin America. We describe the prevalence and transmissibility of integrase HIVDRM in a historical cohort of INSTI-naïve HPW from Argentina (n=56) with Next Generation Sequencing (NGS). METHODS: Bioinformatics analysis was performed by HyDRA software for 20%, 10%, 5%, 2%, and 1% sensitivity thresholds. We calculated the mutational viral load for each INSTI-HIVDRM, considering those with >1000 c/mL as of high risk of transmissibility. RESULTS: The predominant HIV subtype was BF (78.5%). Major HIVDRM were not detected with the population sequencing 20% filter. With a 1% threshold, the prevalence increased to 8.9%; Y143C/S, E92G, E138K, and T66I mutations were found. The median (range) mutational load (expressed in c/mL) was: 355 (50.2-11705); with only 1 case >1000 c/mL Accessory mutations (G163R/K, T97A) were detected mostly with a 20% sensitivity threshold with an overall prevalence of 23.2%; the median (IQR) mutational load was: 23929 (4009-63158) c/mL; all of them above 1000 c/mL. CONCLUSIONS: Our results show evidence of the presence of major INSTI-HIVDRM as aleatory mutations and a high frequency of accessory mutations with potential transmissibility in HPW.
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PURPOSE: To determine the incidence of non-alcoholic fatty liver disease (NAFLD) by non-invasive methods in people living with HIV (PLWH). METHODS: Prospective cohort, in PLWH naïve to antiretroviral therapy, starting bictegravir (BIC) or dolutegravir (DTG) at the Hospital de Infectología "La Raza", in Mexico City, from February 2021 to August 2023. We measured at baseline and 48 weeks triglycerides and glucose index (TyG), fatty liver index (FLI), hepatic steatosis index (HSI) and liver ultrasonography; relative risk (RR) for developing NAFLD was determined. RESULTS: At 48 weeks, TyG index in BIC-group 4.54 (IQR 4.36-4.75), in DTG-group 4.66 (IQR 4.49-4.80), p = .080; HSI in BIC-group 30.30 (IQR 28.12-33.70), in DTG-group 30.85 (IQR 28.02-34.50), p = .650; FLI in BIC-group 14.88 (IQR 7.91-31.80), in DTG-group 19.49 (IQR 8.49-32.28), p = .729; NAFLD was detected by US in 6 [10.3% (95%CI 4.8%-20.7%)] in BIC-group and, 7 [10.9% (95%CI 6.4%-20.9%)] in DTG-group, p = .916. Risk factors for NAFLD development were baseline BMI ≥25 kg/m2, baseline HDL-c <40 mg/dL, and FIB-4 >1.3 at 48 weeks. CONCLUSION: There is a high incidence of NAFLD in PLWH who start a second generation INSTI at 48 weeks; baseline overweight, low HDL-cholesterol and FIB-4 >1.3 at 48 weeks of treatment were independent risk factors for NAFLD development.
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Since HIV was identified as the etiological agent of AIDS, there have been significant advances in antiretroviral therapy (ART) that has reduced morbidity/mortality. Still, the viral genome's high mutation rate, suboptimal ART regimens, incomplete adherence to therapy and poor control of the viral load generate variants resistant to multiple drugs. Licensing over 30 anti-HIV drugs worldwide, including integrase inhibitors, has marked a milestone since they are potent and well-tolerated drugs. In addition, they favor a faster recovery of CD4+ T cells. They also increase the diversity profile of the gut microbiota and reduce inflammatory markers. All of these highlight the importance of including them in different ART regimens.
Research on HIV/AIDS has been focused on finding ways to prevent or cure the disease. One important class of drugs called integrase inhibitors has gained attention. These drugs are effective and have been widely used in the past decade to treat HIV. Integrase inhibitors help in the recovery of immune cells and improve the diversity of gut bacteria while reducing inflammation. It is important to include these drugs in treatment regimens for people living with HIV.
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Fármacos Anti-HIV , Infecções por HIV , Humanos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Inibidores de Integrase/uso terapêutico , Infecções por HIV/tratamento farmacológicoRESUMO
BACKGROUND: The use of integrase inhibitor-based antiretroviral therapy could be associated with worse weight and metabolic outcomes in patients with HIV infection. METHODS: PubMed, EMBASE, and Scopus were searched from inception to March 2022. We selected randomized controlled trials (RCTs) comparing integrase inhibitors with other antiretroviral classes (efavirenz-based or protease inhibitor-based therapies) in naïve HIV patients. Random effects meta-analysis was used to assess the effects of integrase inhibitors vs. controls on weight and lipid outcomes. Effects were described as mean differences (MD) and their 95% confidence intervals (CI). Certain pieces of evidence (CoE) were evaluated using the GRADE methodology. RESULTS: Six RCTs (n = 3521) were included, with patients followed up between 48 and 96 weeks. The use of integrase inhibitors in comparison with other antiretroviral classes was associated with an increase in weight (MD 2.15 kg, 95%CI 1.40 to 2.90, I2 = 0%, moderate CoE), and decreases in total cholesterol (MD -13.44 mg/dL, 95%CI -23.49 to -3.39, I2 = 96%, low CoE), LDL cholesterol (MD -1.37 mg/dL, 95%CI -19.24 to -3.50, I2 = 83%, low CoE), HDL cholesterol (MD -5.03 mg/dL, 95%CI -10.61 to 0.54, I2 = 95%, low CoE), and triglycerides (MD -20.70 mg/dL, 95%CI -37.25 to -4.15, I2 = 92%, low CoE). There was a high risk of bias in two RCTs and some concerns about bias in two RCTs. CONCLUSIONS: In HIV patients, the use of integrase inhibitor-based therapy in comparison with protease inhibitor- or NNRTI-based therapy was associated with a small increase in weight and small decreases in lipid serum levels.
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OBJECTIVES: We assessed real-world weight change and pregnancy outcomes among pregnant women living with HIV who used integrase strand transferase inhibitor (INSTI)-based combined antiretroviral therapy (cART). METHODS: In a retrospective cohort study from 2014 to 2021 for prevention of perinatal HIV infection, we evaluated changes in weight from the first prenatal visit to near delivery for two groups. The categories of change were: low (< 0.18 kg/week), normal (0.18-0.59 kg/week), and high (> 0.59 kg/week). The backbones were lamivudine + tenofovir disoproxil or lamivudine + zidovudine. The comparison groups were women with body mass index (BMI) < 25 kg/m2 versus BMI ≥ 25 kg/m2 and INSTI-naïve versus INSTI-experienced. Continuous variables were analysed with a Kruskal-Wallis test and count or categorical data with χ2 tests. RESULTS: We enrolled 198 pregnant women. At study entry, 74 had BMI < 25 kg/m2 and 124 had BMI ≥ 25 kg/m2 . Excess gestational weight gain was more frequent among women who were INSTI-naïve among both BMI groups (< 25 and ≥ 25). However, the proportion of participants per weight change category was only significantly different between INSTI-naïve women with baseline BMI < 25 kg/m2 and INSTI-experienced women with BMI < 25 kg/m2 . In particular, INSTI-naïve women with BMI < 25 kg/m2 had significantly higher rates of excess gestational weight gain (31.6%) compared with participants with BMI < 25 kg/m2 who conceived while on INSTIs (11.8%, p = 0.004). Rates of unfavourable pregnancy outcomes were low and did not differ significantly between groups. CONCLUSIONS: INSTI-naïve participants with BMI < 25 kg/m2 gained more weight during pregnancy than participants with BMI ≥ 25 kg/m2 who conceived while using INSTIs. Rates of adverse pregnancy outcomes did not differ between the groups.
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Fármacos Anti-HIV , Ganho de Peso na Gestação , Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , Humanos , Feminino , Gravidez , Masculino , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Gestantes , Estudos Retrospectivos , Fármacos Anti-HIV/uso terapêutico , Aumento de Peso , Inibidores de Integrase de HIV/uso terapêutico , Resultado da GravidezRESUMO
Resumen Introducción: en pacientes con virus de inmunodeficiencia humana algunos antirretrovirales afectan el perfil lipídico incrementando el riesgo cardiovascular. Hay evidencia de que los inhibidores de integrasa afectan poco al perfil lipídico. El presente estudio buscó evaluar la mejor evidencia disponible sobre cambios en lípidos de pacientes con virus de inmunodeficiencia humana que cambiaron su terapia antirretroviral a esquemas con inhibidores de integrasa. Métodos: revisión sistemática de la literatura con intención metaanalítica. A partir de la pregunta: "En pacientes mayores de 16 años con virus de inmunodeficiencia humana, los esquemas antirretrovirales que incluyen inhibidores de integrasa comparados con aquellos esquemas antirretrovirales que no los incluyen, ¿presentan cambios en el perfil lipídico?" se extrajeron palabras clave para búsqueda de la evidencia publicada entre 1997 y diciembre 2019. Se incluyeron estudios experimentales y observacionales y su calidad fue evaluada. Se realizó análisis por inhibidor de integrasa y parámetro lipídico buscándose síntesis cuantitativa de la evidencia. Resultados: se identificaron 17 estudios relevantes susceptibles de síntesis de la evidencia con un total de 5 683 pacientes. De estos, 2 878 entraron a síntesis cuantitativa. Acorde a lo encontrado, los inhibidores de integrasa presentan mejor perfil lipídico comparados a otros antirretrovirales. Dolutegravir fue el que mostró mejor perfil lipídico cuando la comparación se hizo con inhibidores de proteasa. Raltegravir tuvo mejor perfil lipídico comparándolo con inhibidores de transcriptasa inversa no análogos de nucleósidos. Conclusiones: el uso de inhibidores de integrasa es un factor relevante en el control del riesgo cardiovascular en pacientes con virus de inmunodeficiencia humana.
Abstract Introduction: some antiretrovirals affect the lipid profile in human immunodeficiency virus patients increasing their cardiovascular risk. Integrase inhibitors generate little lipid alteration. The present study evaluated the best available evidence about changes in the lipid profile in human immunodeficiency virus patients who had switch from different antiretroviral therapies to schemes with integrase inhibitors. Methods: a systematic review with meta-analytic intention was carried out. From the question "How does antiretroviral schemes with integrase inhibitors impact in lipid profile in human immunodeficiency virus patients compared to antiretroviral schemes without integrase inhibitors?" an evidence search was done. Articles from experimental and observational studies were included and the quality was evaluated. An analysis by integrase inhibitor and lipid parameters was performed. Results: 17 relevant studies were identified and 2 878 patients were included in the quantitative synthesis. According to evidence, integrase inhibitors had a better lipid profile compared to other antiretrovirals. Dolutegravir had a better metabolic profile when it was compared with protease inhibitors. Raltegravir had a better lipid profile when it was compared to non-nucleoside analog reverse transcriptase inhibitors. Conclusions: integrase inhibitors are a relevant factor for cardiovascular risk control in patients with human immunodeficiency virus.
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Few studies have compared the clinical efficacy and adverse events of combined antiretroviral therapy (cART) regimens in pregnant women seeking obstetrical care. The objective of this study was to compare the efficacy (virus load response), adverse events, and obstetrical and neonatal outcomes of three different regimens of cART in HIV-infected pregnant women initiating treatment in Rio de Janeiro, Brazil. This was a retrospective cohort study of cART-naive pregnant women who initiated either ritonavir-boosted protease inhibitors (atazanavir or lopinavir), efavirenz, or raltegravir plus a backbone regimen. From 2014 to 2018, 390 pregnant women were followed over time. At baseline, the median viral load (VL) for HIV was 4.1 log copies/ml. Among participants who received cART for 2 to 7 weeks, the VL decline was greater for raltegravir (2.24 log copies/ml) than for efavirenz or protease inhibitors (P < 0.001). Virologic suppression was achieved in 87% of women on raltegravir near delivery versus 73% on efavirenz and 70% on protease inhibitors (P = 0.011). Patients on raltegravir achieved virologic suppression faster than those on other regimens (P = 0.019). Overall, the HIV perinatal infection rate was 1.5%. This clinical study compared three potent and well-tolerated cART regimens and demonstrated that a higher proportion of participants on raltegravir achieved an undetectable HIV VL near delivery (P = 0.011) compared to the other arms. These findings suggest that raltegravir-containing regimens are optimal regimens for women with HIV initiating treatment late in pregnancy.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Complicações Infecciosas na Gravidez , Fármacos Anti-HIV/uso terapêutico , Brasil , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Carga ViralRESUMO
INTRODUCTION: As integrase inhibitors become available in low- and middle-income countries (LMICs), they offer the potential to expand extremely limited treatment options available to children and adolescents. In LMICs, only small numbers have used raltegravir, primarily as part of third-line regimens. Using data from the IeDEA global consortium, we aimed to describe the characteristics of children on raltegravir-containing regimens and their outcomes. METHODS: We included data from 1994 to 2017 from children (age <18 years), from East and Southern Africa, Asia and South America, who received cART regimens containing raltegravir for ≥90 days. We describe their characteristics at raltegravir start, and their immunological and virological outcomes. RESULTS AND DISCUSSION: In total, 62 children were included, with median age at raltegravir initiation of 14.3 years (IQR 11.2 to 15.8) and median CD4 count of 276 cells/µL (IQR 68 to 494). Among 40 (65%) with drug resistance testing prior to raltegravir, 71% were resistant to at least one protease inhibitor (PI), and 32% had high-level resistance to at least one drug class. Most (n = 50; 81%) received raltegravir as part of third-line cART following PI-based regimens, and were on regimens containing four or more drugs (n = 47, 76%). By database closure, median duration on raltegravir was 2.0 years (IQR 0.8 to 3.0), 1 (1.6%) patient had died, 6 (9.7%) were lost to follow-up and 21 (34%) had discontinued raltegravir. Among 15 patients reporting reasons for stopping raltegravir, six discontinued because it was no longer available. Within one year of starting raltegravir, among 53 patients with VL measures, 40 (75%) had VL < 1000 copies/mL, and among 54 with a reported CD4 count, 45 (83%) and 36 (67%) were ≥350 and ≥500 cells/µL, respectively, with median CD4 count increasing to 517.5 cells/µL (IQR 288 to 810). CONCLUSIONS: Among children in LMICs, the initial use of raltegravir has been primarily for post PI-based cART. We found good virological and immunological outcomes despite frequent prior triple-class failure and high levels of drug resistance. Both access to raltegravir and long-term adherence to regimens with large pill-burdens remain challenging. Policies which promote earlier access to new drugs and simplify daily regimens for children and adolescents in LMICs are needed.
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Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Raltegravir Potássico/uso terapêutico , Adolescente , África Austral , Ásia , Contagem de Linfócito CD4 , Criança , Feminino , Infecções por HIV/economia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pobreza , América do Sul , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: In resource-limited settings, multi-experienced HIV infected patients are often prescribed raltegravir for salvage therapy. Patients failing raltegravir-containing regimens require other drugs including other integrase inhibitors. In this context, real-life data about the resistance and cross-resistance pathways between integrase inhibitors is limited. The aim of this study was to investigate integrase resistance pathways in a cohort of Mexican multi-experienced patients failing of a raltegravir-containing salvage regimen. METHODS: Twenty-five plasma samples from subjects failing antiretroviral regimens which included raltegravir were obtained from various healthcare centres from 2009 to 2017 in Mexico. Antiretroviral history and demographics were collected. Samples were processed for integrase resistance genotyping testing by sequencing. The viral sequences were analysed with the Stanford HIV drug resistance database algorithm. Data was analysed with SPSS Statistics software. RESULTS: We found a mean viral load of 4.17 log10 c/mL (SD 1.11) at the time of virologic failure. Forty-eight percent of the samples were raltegravir resistant. The Y143R/H/C substitutions were the most prevalent, followed by the N155H, and both Q148H/K and G140S/A in the same proportion. The Q148 + G140 combination was found in (12%) of the samples. Cross-resistance to elvitegravir was found in 83.3% and in 18.2% for both dolutegravir and bictegravir. Thirteen samples (52%) were susceptible to the four integrase strand-transfer inhibitors. CONCLUSIONS: Our findings suggest a high occurrence of resistance and cross-resistance to other integrase inhibitors among multi-experienced subjects failing raltegravir. We found a modestly lower proportion of cross-resistance to dolutegravir than data from clinical trials. Likely this drug could be used for salvage therapy. Explanations for the absence of mutations in half of the samples, other than reduced adherence, should be further investigated. Close surveillance is needed.
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Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/genética , Estudos de Coortes , Estudos Transversais , Feminino , Infecções por HIV/virologia , Integrase de HIV/genética , Soropositividade para HIV , Humanos , Masculino , México , Raltegravir Potássico/uso terapêutico , Análise de Sequência de DNA , Falha de Tratamento , Carga Viral/efeitos dos fármacosRESUMO
La Guía Colombiana de práctica clínica para la atención de la infección por VIH / Sida en adolescentes y adultos incluye como primera línea de tratamiento el uso de Inhibidores de integrasa; sin embargo, no incluye recomendaciones que soporten la decisión de tratar a los pacientes controladores elite (CE). La definición de controladores elite es confusa pues varía de un estudio a otro y se desconoce si las recomendaciones de tratamiento, se pueden aplicar a los controladores de forma similar; tampoco existen mecanismos apropiados para el seguimiento sistemático de los controladores elite cuando se inicia en ellos una terapia antirretroviral. Este artículo es una revisión bibliográfica de la información disponible sobre la definición de los pacientes controladores, y los controladores elite, su evolución clinica e inmunológica, el tratamiento y las terapias disponibles en Colombia.
The Colombian Guide to Clinical Practice for HIV / AIDS Care in Adolescents and Adults, includes as first line of treatment the use of integrase inhibitors; however, there is no information to support the decision to treat elite control patients (EC). The definition of elite controller is confusing, because of the changes in definitions between studies, and it is unknown whether these recommendations apply to these patients in a similar way; and how should be systematic follow-up of elite controllers when antiretroviral therapy is initiated. Present paper is a bibliographic review of the available information on the definition of the controllers, and elite controllers its clinical and immunological evolution, the treatment and therapies available in Colombia.
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Síndrome da Imunodeficiência Adquirida , HIV , Guia de Prática Clínica , Inibidores de Integrase , Evolução Clínica , Revisão , Controle de Infecções , Assistência ao Convalescente , Integrases , InfecçõesRESUMO
Los inhibidores de transferencia de la cadena de integrasa (INSTI) son medicamentos cuyo mecanismo de acción consiste en bloquear el proceso de integración del ADN proviral al ADN del hospedero mediante la unión al sitio catalítico de la integrasa viral y de esta manera evitar su replicación. Actualmente se cuenta con la aprobación INSTI de primera y segunda generación, presentan similitud en su mecanismo de acción, cambios en su estructura que modifican su barrera genética, pero mantienen su perfil de seguridad y efectividad. Desde su aprobación en el año 2007, se han llevado a cabo múltiples estudios clínicos cuyos resultados han permitido avanzar en el conocimiento de su efectividad en diferentes escenarios clínicos; (pacientes naive, experimentados, esquemas de simplificación y profilaxis, así, como en el conocimiento de su perfil de mutaciones de resistencia). En el presente artículo se hizo una revisión de los miembros de esta familia de antirretrovirales (ARV).
Integrase strand transfer inhibitors (INSTI) are drugs whose mechanism of action consists of blocking the integration process of the proviral DNA to the host DNA by binding to the catalytic site of the viral integration and thus preventing its replication. Currently it has the approval of INSTI of first generation, two of second generation and in process of approval of a third of second generation. The two generations has similitude in its mechanisms of action, changes in its structures that modify its genetic barrier, but keeping his security and effectiveness profile. Since the approval of INSTI´s in 2007 to date, multiple clinical studies have been carried out, whose results have allowed us to advance in the knowledge of their effectiveness in different clinical scenarios; (naive patients, experienced patients, simplification and prophylaxis schemes, as well as in the knowledge of their profile of resistance mutations). In the present article, we made a review of the members of this family of antiretrovirals (ARV).
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Humanos , Masculino , Feminino , DNA , Inibidores de Integrase , Características da Família , HIV , Revisão , Antirretrovirais , MutaçãoRESUMO
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.
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Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Pirrolidinonas/uso terapêutico , Adulto , Feminino , Genótipo , HIV-1/classificação , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Oxazinas , Piperazinas , Piridonas , Raltegravir Potássico , Terapia de Salvação/métodos , Análise de Sequência de DNA , Falha de Tratamento , Adulto JovemRESUMO
This review will summarize the role of integrase in HIV-1 infection, the mechanism of integrase inhibitors and resistance with an emphasis on raltegravir (RAL), the first integrase inhibitor licensed to treat HIV-1 infection.