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The recently Food and Drug Administration (FDA)-approved cabotegravir (CAB) has demonstrated efficacy as an antiretroviral agent for HIV treatment and prevention, becoming an important tool to stop the epidemic in the United States of America (USA). However, the effectiveness of CAB can be compromised by the presence of specific integrase natural polymorphisms, including T97A, L74M, M50I, S119P, and E157Q, particularly when coupled with the primary drug-resistance mutations G140S and Q148H. CAB's recent approval as a pre-exposure prophylaxis (PrEP) may increase the number of individuals taking CAB, which, at the same time, could increase the number of epidemiological implications. In this context, where resistance mutations, natural polymorphisms, and the lack of drug-susceptibility studies prevail, it becomes imperative to comprehensively investigate concerns related to the use of CAB. We used molecular and cell-based assays to assess the impact of T218I and T218S in the context of major resistance mutations G140S/Q148H on infectivity, integration, and resistance to CAB. Our findings revealed that T218I and T218S, either individually or in combination with G140S/Q148H, did not significantly affect infectivity, integration, or resistance to CAB. Notably, these polymorphisms also exhibited neutrality concerning other widely used integrase inhibitors, namely raltegravir, elvitegravir, and dolutegravir. Thus, our study suggests that the T218I and T218S natural polymorphisms are unlikely to undermine the effectiveness of CAB as a treatment and PrEP strategy.
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Background: Currently, integrase inhibitors (INIs)-based ART regimens are the preferred initial therapy for AIDS patients. There is scarce information on the use of dolutegravir (DTG) among late-presenter people living with HIV (PLHIV). Objectives: To compare the effect of DTG- or efavirenz (EFV)-based regimens on the outcomes of patients with advanced AIDS. Methods: We compared two cohorts of consecutive symptomatic AIDS patients (WHO stage 4, CD4 count<50 cells/mL) starting therapy with DTG-based (2018-2021, prospective cohort) or EFV-based regimens (2013-2016, retrospective cohort) from five Brazilian cities. The main endpoints were early (all-cause) mortality, viral suppression at 24 and 48 weeks, changes in CD4 count, and changes in initial therapy (for any reason). Results: We included all eligible patients in a consecutive way (in both groups) until we reached 92 individuals per arm. The median baseline CD4 count (20 vs. 21 cells/mL) and the median HIV plasma viral load (5.5 copies/mL log10) were identical across the groups. Viral suppression rates were higher in the DTG group than in the EFV group at 24 (67.4% vs. 42.4%,) and 48 weeks (65.2% vs. 45.7%, p < 0.001 for both comparisons). More patients in the DTG group presented with CD4 > 200 cells/mL compared to the EFV group at 48 weeks (45% vs. 29%, p = 0.03). Treatment changes (ITT, M = F) were significantly more frequent in the EFV group (1% vs. 17%, p < 0.0001). The relative mortality rate was 25% lower in the DTG group, but without statistical significance. Conclusion: We detected a higher rate of virological suppression and greater treatment durability in patients with advanced AIDS treated with DTG than in those treated with EFV.
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Introducción: a pesar de los avances en tratamiento antirretroviral, existe la posibilidad de que personas que viven con el virus de la inmunodeficiencia humana (VIH) experimenten falla terapéutica vinculada a múltiples factores que impactan en la respuesta al fármaco. Objetivos: evaluar la utilidad de aplicar un modelo farmacocinético en pacientes con diagnóstico de VIH en tratamiento con dolutegravir para el análisis de las concentraciones plasmáticas experimentales. Adicionalmente, se pretende identificar potenciales interacciones farmacológicas, evaluar adherencia y fallo terapéutico. Material y método: se realizó un estudio piloto transversal y observacional en pacientes VIH tratados con dolutegravir que incluyó la dosificación de la concentración plasmática, evaluación de adherencia mediante el cuestionario simplificado de adherencia a la medicación (SMAQ) y retiro de medicación. Se utilizó un modelo poblacional referenciado en la bibliografía para la predicción de concentraciones de dolutegravir en cada paciente y se compararon con las concentraciones experimentales. Resultados: fueron incluidos en el estudio 21 pacientes. Al cotejar las concentraciones plasmáticas experimentales con la simulación farmacocinética se encontraron diferencias para 12 pacientes, las cuales se explican por posibles interacciones farmacológicas, mala adherencia u otros factores que afectan la farmacocinética. Se detectó 38% de no adherencia de acuerdo con SMAQ y 23% de acuerdo con el retiro de medicación. Conclusiones: se expone el rol potencial de los modelos farmacocinéticos para la interpretación de concentraciones plasmáticas y se genera la necesidad de avanzar en este tipo de estudios para el establecimiento de rango terapéutico y aplicabilidad clínica.
Introduction: Despite advances in antiretroviral treatment, there is a possibility that people living with HIV may experience treatment failure linked to multiple factors that impact drug response. Objective: To evaluate the usefulness of applying a pharmacokinetic model in patients diagnosed with HIV undergoing treatment with dolutegravir for the analysis of experimental plasma concentrations. Additionally, the aim is to identify potential drug interactions, assess adherence, and therapeutic failure. Method: A cross-sectional, observational pilot study was conducted in HIV patients treated with dolutegravir, which included plasma concentration dosing, assessment of adherence using the Simplified Medication Adherence Questionnaire (SMAQ), and medication withdrawal. A population-based model referenced in the literature was used to predict dolutegravir concentrations in each patient and these were compared with experimental concentrations. Results: Twenty-one patients were included in the study. When comparing experimental plasma concentrations with pharmacokinetic simulation, differences were found for 12 patients, which can be explained by possible drug interactions, poor adherence, or other factors affecting pharmacokinetics. Non-adherence was detected in 38% according to the SMAQ and 23% according to medication withdrawal. Conclusions: The potential role of pharmacokinetic models in the interpretation of plasma concentrations is highlighted, emphasizing the need to advance in this type of studies to establish therapeutic ranges and clinical applicability.
Introdução: Apesar dos avanços no tratamento antirretroviral, existe a possibilidade de que pessoas que vivem com HIV experimentem falha terapêutica ligada a múltiplos fatores que impactam na resposta ao medicamento. Objetivos: Avaliar a utilidade da aplicação de um modelo farmacocinético em pacientes com diagnóstico de HIV em tratamento com dolutegravir para análise de concentrações plasmáticas experimentais. Além disso, pretende-se identificar potenciais interações medicamentosas, avaliar a adesão e a falha terapêutica. Método: Um estudo piloto observacional transversal foi conduzido em pacientes HIV tratados com dolutegravir que incluiu dosagem de concentração plasmática, avaliação de adesão usando o questionário simplificado de adesão à medicação (SMAQ) e retirada da medicação. Um modelo populacional referenciado na literatura foi utilizado para prever as concentrações de dolutegravir em cada paciente e compará-las com as concentrações experimentais. Resultados: 21 pacientes foram incluídos no estudo. Ao comparar as concentrações plasmáticas experimentais com a simulação farmacocinética, foram encontradas diferenças em 12 pacientes, que são explicadas por possíveis interações medicamentosas, má adesão ou outros fatores que afetam a farmacocinética. Foram detectadas 38% de não adesão segundo o SMAQ e 23% segundo retirada da medicação. Conclusões: Fica exposto o papel potencial dos modelos farmacocinéticos para a interpretação das concentrações plasmáticas e gera-se a necessidade de avançar neste tipo de estudos para estabelecer a faixa terapêutica e a aplicabilidade clínica.
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Terapia Antirretroviral de Alta Atividade , Antirretrovirais/farmacocinética , Interações Medicamentosas , Cooperação e Adesão ao TratamentoRESUMO
BACKGROUND: Excessive weight gain is a current concern among People Living with HIV (PLHIV) starting ART. OBJECTIVES: To evaluate the weight gain after 48-weeks of ART in naive patients, according with baseline CD4 count. METHODS: PLHIV starting 3TC + TDF + DTG with at least 48-weeks of follow up in two AIDS referral centers were stratified by baseline CD4 count (lower or higher than 200 cells/mm3). Data on CD4 count, HIV viral load, weight/Body Mass Index (BMI), lipids and glucose levels were collected at baseline, 24 and 48 weeks of treatment. For analysis purpose, patients were categorized according to their BMI progression. RESULTS: A total of 270 patients were included in the study. Mean CD4 count were 78.3 ± 61.7 and 536.7 ± 273 cells/mm3 for low and high CD4 count groups, respectively (p < 0.001). Baseline BMI was significantly lower in low CD4 group (21.7 vs. 23.6 Kg/m2, p < 0.001). Patients in low CD4 group gained more weight than those in high CD4 group (11.2 ± 8.5 kg vs. 2.2 ± 4.2 Kg, p = 0.004). Overall weight gain was higher in women, regardless group (13.1 ± 7.9 Kg vs. 1.4 ± 3.6 Kg for women and men, respectively, p < 0.001). The proportion of overweight/obesity significantly increased in low CD4 group. Viral suppression rate was high for both groups. At week 48 the overall proportion of overweight/obesity was like that reported for the Brazilian population. CONCLUSIONS: Weight gain in the present study indicates a "return to health" phenomenon. Excessive weight gain was more frequent in women.
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Fármacos Anti-HIV , Infecções por HIV , Masculino , Humanos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Sobrepeso/tratamento farmacológico , Seguimentos , Aumento de Peso , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Contagem de Linfócito CD4 , Fármacos Anti-HIV/efeitos adversosRESUMO
BACKGROUND: Since January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine with dolutegravir (TL + D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. We evaluated the HIV antiretroviral genotypic resistance profile of patients referred for genotyping in the public health system who failed first-line TL + D after at least six months of therapy on or before December 31, 2018. METHODS: HIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL + D in the Brazilian public health system before December 31, 2018. RESULTS: One hundred thirteen individuals were included in the analysis. Major INRAMs were detected in seven patients (6.19%), four with R263K, one with G118R, one with E138A, and one with G140R. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. Sixteen (14.2%) additional individuals presented minor INRAMs, and five (4,42%) patients had both major and minor INRAMS. Thirteen (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients, respectively. Mutations not related to TL + D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors. CONCLUSIONS: In marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL + D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.
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Infecções por HIV , Inibidores da Transcriptase Reversa , Humanos , Brasil , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Mutação , Antirretrovirais , Tenofovir , Falha de Tratamento , Infecções por HIV/tratamento farmacológicoRESUMO
OBJECTIVE: To measure the incidence of neuropsychiatric adverse drug reactions (ADRs) in individuals living with HIV who initiated antiretroviral therapy (ART) with first-line regimens containing dolutegravir (DTG) or efavirenz (EFV) and associated factors. METHODS: Prospective cohort study with individuals living with HIV who started ART with DTG or EFV associated with tenofovir disoproxil and lamivudine in Belo Horizonte, Brazil. Sociodemographic, clinical, and laboratory data were collected from September 2015 to October 2018 in three specialized HIV care services through interviews, clinical records, and computerized systems. We analysed the frequency of neuropsychiatric ADRs recorded in clinical records 12 months after starting antiretroviral use, and the associated factors were investigated using binary logistic regression. RESULTS: A total of 152 (35.1%) of the 433 individuals included had neuropsychiatric ADRs. The incidence density was 35.3/100 person-years. The subjects mainly had sleep disorders and disturbances (21.3%), neurological disorders (13.9%), headaches (8.1%), and anxiety disorders and symptoms (3.0%), more frequently in individuals using EFV. A lower likelihood of neuropsychiatric ADRs was associated with using a DTG-based antiretroviral regimen (OR = 0.24; 95% CI = 0.14-0.40) and anxiety or depression signs and symptoms at the onset of treatment (OR = 0.57; 95% CI = 0.37-0.89). CONCLUSION: The incidence of neuropsychiatric ADRs was high in individuals starting ART with a lower likelihood of using a DTG-based regimen. The DTG-based regimen had a better safety profile for neuropsychiatric ADRs than the EFV-based regimen.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Infecções por HIV , Humanos , Estudos Prospectivos , Brasil , Infecções por HIV/tratamento farmacológico , Benzoxazinas/efeitos adversosRESUMO
A quantitative descriptive study based on Brazilian Active Pharmacovigilance of Dolutegravir (DTG) Project was performed to describe the adverse drug reactions (ADRs) to DTG reported and to evaluate the noncompleteness of data from DTG active pharmacovigilance in Brazil. ADRs and clinical and individual data were obtained from information from the Pharmacovigilance Questionnaire from April 2017 to August 2019. The reported ADRs were classified using the Medical Dictionary for Regulatory Activities (MedDRA). In the evaluated period, 249,066 individuals using DTG participated in the active pharmacovigilance of DTG, with 3472 (1.39%) reporting ADRs at least once. A total of 6312 ADRs were reported, of which 57.56% were persistent and 81.46% were not serious according to the individuals' reports. Most of the reported ADRs were gastrointestinal, neurological and psychiatric. ADRs related to neural tube defects and serious neuropsychiatric ADRs have been reported. Completion of more than half of the fields in the Pharmacovigilance Questionnaire was excellent. The frequency of ADR was low in relation to the number of people living with HIV (PLHIV) using DTG in Brazil, which suggests good tolerability and safety of DTG. The DTG active pharmacovigilance database in Brazil showed good data completeness.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Infecções por HIV , Humanos , Brasil , Farmacovigilância , Sistemas de Notificação de Reações Adversas a MedicamentosRESUMO
Levels of adherence to antiretroviral therapy (ART) can affect the likelihood of viral suppression differentially among ART regimens. In this prospective cohort conducted in Belo Horizonte, Brazil, we included 354 individuals who initiated ART containing tenofovir disoproxil fumarate/lamivudine/efavirenz in fixed-dose combination (TDF/3TC/EFV) or tenofovir disoproxil fumarate/lamivudine associated with dolutegravir (TDF/3TC + DTG). Viral suppression (viral load <50 copies/mL) was evaluated within six months of follow-up at different adherence levels and by therapeutic regimen. Adherence was measured by the Proportion of Days Covered (PDC) and classified into low (≤84%), intermediate (85-89%) or high (≥90%). The association between viral suppression, adherence levels, and other explanatory variables was analyzed using chi-square and multivariable logistic regression. Viral suppression was achieved by 76.0% of individuals and was more frequent among those who achieved higher levels of adherence (high adherence: 79.3%, intermediate: 71.4% and low: 45.2%), those on TDF/3TC + DTG, and those who had viral load ≤100,000 copies/mL at the onset of treatment (p < 0.05). Moreover, individuals on TDF/3TC + DTG had an approximately 90% probability of achieving viral suppression at intermediate adherence levels. These results add new insights on the possibility of lower adherence levels for contemporary antiretroviral regimens currently used as first-line therapy worldwide.
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Fármacos Anti-HIV , Infecções por HIV , Humanos , Lamivudina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Brasil , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Estudos Prospectivos , Antirretrovirais/uso terapêutico , Tenofovir/uso terapêutico , Benzoxazinas/uso terapêuticoRESUMO
ABSTRACT Background: Excessive weight gain is a current concern among People Living with HIV (PLHIV) starting ART. Objectives: To evaluate the weight gain after 48-weeks of ART in naive patients, according with baseline CD4 count. Methods: PLHIV starting 3TC + TDF + DTG with at least 48-weeks of follow up in two AIDS referral centers were stratified by baseline CD4 count (lower or higher than 200 cells/mm3). Data on CD4 count, HIV viral load, weight/Body Mass Index (BMI), lipids and glucose levels were collected at baseline, 24 and 48 weeks of treatment. For analysis purpose, patients were categorized according to their BMI progression. Results: A total of 270 patients were included in the study. Mean CD4 count were 78.3 ± 61.7 and 536.7 ± 273 cells/mm3 for low and high CD4 count groups, respectively (p < 0.001). Baseline BMI was significantly lower in low CD4 group (21.7 vs. 23.6 Kg/m2, p < 0.001). Patients in low CD4 group gained more weight than those in high CD4 group (11.2 ± 8.5 kg vs. 2.2 ± 4.2 Kg, p = 0.004). Overall weight gain was higher in women, regardless group (13.1 ± 7.9 Kg vs. 1.4 ± 3.6 Kg for women and men, respectively, p < 0.001). The proportion of overweight/obesity significantly increased in low CD4 group. Viral suppression rate was high for both groups. At week 48 the overall proportion of overweight/obesity was like that reported for the Brazilian population. Conclusions: Weight gain in the present study indicates a "return to health" phenomenon. Excessive weight gain was more frequent in women.
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ABSTRACT Objective To compare viral suppression in treatment-naïve adults starting antiretroviral therapy with dolutegravir (50mg)- and efavirenz (600mg)-based regimens. Methods We analyzed secondary data from Brazilian health information systems of people living with human immunodeficiency virus who started antiretroviral therapy between 2015 and 2017 in Minas Gerais, Brazil. The outcome was viral suppression, defined as the achievement of the first viral load <50 copies/mL within 12 months after initiating antiretroviral therapy. This outcome was also compared with viral load <1,000 copies/mL and analyzed in two scenarios: intention-to-treat versus per-protocol. Time to viral suppression and adjusted odds ratio accompanied by 95% confidence intervals were estimated. Results Of the 2,599 participants enrolled, 77.5% were men, and the median age was 34 years. In the intention-to-treat analysis, viral suppression was 58.1% for efavirenz and 76.7% for dolutegravir. People living with HIV on dolutegravir-based regimen were more likely to achieve viral suppression (aOR: 2.44; 95%CI: 2.01-2.95) and had a shorter median time to viral suppression (p<0.0001). Antiretroviral therapy initiation within <120 days, baseline CD4⁺T-cells ≥200 cells/mm3, and viral load <100,000 copies/mL had higher odds of viral suppression. According to the per-protocol analysis, viral suppression ≥90% was observed by considering viral load <1,000 copies/mL. Conclusion Our study demonstrated that viral suppression improved after introducing dolutegravir, although the proportion of patients with viral load <50 copies/mL was lower than expected. Improved access to routine viral load examinations and continuous surveillance of the effectiveness of antiretroviral therapy should be considered.
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The aim of this study was to investigate adverse reactions to Dolutegravir, a drug recently made available by the Unified Health System (SUS) for treating HIV infections. The frequency, severity and sex distribution of adverse reactions to Dolutegravir were identified over the first 18 months of its availability in users in the state of Paraná. Information was obtained through the pharmacovigilance questionnaire prepared by the Ministry of Health, accessed through the Logistics Control System for Medicines(SICLOM). During the study period, dolutegravirwas dispensed to 9,865 patients in the state. However, 9,207 users (93.3%) answered the pharmacovigilance questionnaire. Among them, 1.75% reported 279 adverse reactions. This population was composed mainly of male people (69.57%), in the ratio of 2.29 men for each woman, white (67.08%), aged between 20 and 29 years (26.71%), single (45.34%) and with education between 8 and 11 years of study (41.61%). Gastrointestinal (36.92%) and nervous system (14.34%) disorders were the most prevalent. 77.78% adverse reactions were considered non-serious by users. It can be concluded that dolutegravirhad a low prevalence of adverse reactions in users in the state of Paraná, demonstrating to be safe for use by the population in therapy against HIV, in accordance with clinical trials.
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Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Antirretrovirais/efeitos adversos , Antirretrovirais/farmacologia , Farmacovigilância , Sistema Único de Saúde , Índice de Gravidade de Doença , Distribuição por Sexo , Inibidores de Integrase de HIV/uso terapêutico , Antirretrovirais/uso terapêuticoRESUMO
Integrase strand-transfer inhibitors (INSTI) are the latest class of antiretrovirals registered in Mexico. They include raltegravir (RAL), elvitegravir/cobicistat (EVG/c), dolutegravir (DTG) and bictegravir (BIC). Along with international guidelines, Mexico adopted the use of INSTI about two years ago as initial antiretroviral therapy (ART). This is partially due to the increase in the pre-treatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI), mainly efavirenz (EFV). Furthermore, INSTI depict greater efficacy, safety and less drug-drug interactions than NNRTI and protease inhibitors (PI). DTG is a second generation INSTI with a high barrier to resistance. It is recommended in international and national guidelines in a wide variety of clinical scenarios for persons living with human immunodeficiency virus (HIV) (PLWHIV), including treatment-naïve, first-line NNRTI treatment failure, simplification switch in suppressed patients, pregnancy, women with childbearing potential, adolescents and children over 6 years of age. DTG is mostly metabolized by the liver UDP-glucuronosyltransferase, and exhibits low drug-drug interactions overall; on the other hand, it has an extremely low renal elimination, therefore may be used in PLWHIV with advanced kidney disease without dose modification. Tuberculosis is a common coinfection in Mexico that requires rifampin-based anti-tuberculosis therapy, which requires increasing DTG to double dosing (50 mg BID). In Mexico, DTG-based regimens are likely to be cost-effective in many scenarios, given its acquisition costs and the particularities of the HIV population and associated clinical conditions, including a relatively high proportion of the following: i) new HIV diagnoses presenting at acquired immunodeficiency syndrome (AIDS) stage; ii) high rate of tuberculosis coinfection; iii) frequent first-line NNRTI treatment failures; and iv) relatively high proportion of infected children and adolescents.
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Infecções por HIV , Inibidores de Integrase de HIV , HIV-1 , Adolescente , Custos e Análise de Custo , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , México/epidemiologia , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Raltegravir PotássicoRESUMO
The HIV-1 integrase viral protein is responsible for incorporating the viral DNA into the genomic DNA. The inhibition of viral integration into host cell DNA is part of recent therapeutic procedures. Combination therapy with protease and reverse transcriptase inhibitors has demonstrated good synergistic results in reducing viral replication. The purpose of this study is to assess the occurrence of integrase drug resistance mutations from the period comprising 2013 through 2018 in Puerto Rico (PR). We analyzed 131 nucleotide sequences available in our HIV genotyping database, and we performed drug resistance mutation analyses using the Stanford HIV Drug Resistance Database. Twenty-one sequences (16.03%) harbored major or resistance-associated mutations. We identified the Q148HKR, G140S, Y143R, N155H, S147G, and E138EA major drug resistance mutations and the D232DN, T97TA, E157Q, G163GART accessory mutations. We detected high-level drug resistance to Elvitegravir and Raltegravir (76.19% and 85.71%). Moreover, we identified sequences harboring drug resistance mutations that could provide resistance to Dolutegravir. The transmission of strains with integrase antiretroviral resistance has been previously documented in treatment naïve patients. Given the increase of patients treated with integrase inhibitors, surveillance of drug resistance mutations is an essential aspect of PR's clinical management of HIV infection.
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Infecções por HIV , Inibidores de Integrase de HIV , HIV-1 , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , Humanos , Mutação , Porto Rico/epidemiologia , PiridonasRESUMO
Dolutegravir (DTG) is amongst the most prescribed antiretrovirals worldwide and is recommended as first line regimen in most HIV treatment guidelines. Its use, although infrequently, had been associated to an increased chance of neural tube defects (NTD) in Botswana, Africa. Herein we describe two cases of NTD in women who conceived while taking DTG as part of their antiretroviral treatment in the city of Porto Alegre, Brazil.
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Infecções por HIV , Defeitos do Tubo Neural , África , Brasil , Feminino , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis , Humanos , Oxazinas , Piperazinas , PiridonasRESUMO
ABSTRACT Dolutegravir (DTG) is amongst the most prescribed antiretrovirals worldwide and is recommended as first line regimen in most HIV treatment guidelines. Its use, although infrequently, had been associated to an increased chance of neural tube defects (NTD) in Botswana, Africa. Herein we describe two cases of NTD in women who conceived while taking DTG as part of their antiretroviral treatment in the city of Porto Alegre, Brazil.
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Humanos , Feminino , Infecções por HIV/tratamento farmacológico , Defeitos do Tubo Neural , Oxazinas , Piperazinas , Piridonas , Brasil , África , Compostos Heterocíclicos com 3 AnéisRESUMO
Los inhibidores de integrasa constituyen la terapia de elección en el tratamiento antirretroviral de inicio en adultos y adolescentes con infección por el virus de inmunodeficiencia humana (VIH), sin embargo, el Dolutegravir (DTG) tiene indicación reciente en la población pediátrica. Objetivo: Describir la experiencia preliminar de pacientes pediátricos con infección VIH en tratamiento con DTG. Método: Se realizó un estudio descriptivo y prospectivo en pacientes pediátricos infectados con VIH, evaluados en el Hospital de Niños JM de los Ríos (Caracas-Venezuela) desde febrero hasta junio 2019. Se evaluaron criterios de indicación DTG, parámetros virológicos e inmunológicos y aparición de efectos adversos. Para el análisis se utilizaron la base de datos Acces 2004 y programa estadístico Epi-Info 7 y los resultados fueron presentados en tablas de frecuencia y porcentaje. Resultados: De 193 pacientes el 56,5 % (n=109) son adolescentes y el 9.2 % (n=10) recibió DTG coformulado. El 60 % pertenecen al género masculino. Se registró como edad una moda de 15,6 años y un peso promedio de 40,75 Kg. El 50 % recibió DTG por no disponer del esquema de TARV previo y solo el 10 % como inicio de TARV. El 70 % no presentó efectos adversos, los presentados fueron leves. Solo el 20 % de los pacientes contaban con carga viral y sub-población linfocitaria previo al inicio DTG sin control posterior. Conclusiones: La principal indicación de DTG fue el reinicio de la terapia antirretroviral por no disponibilidad de esquema anterior. El 70 % de los pacientes no presentaron efectos adversos a la terapia.
Integrase inhibitors constitute the therapy of choice in the antiretroviral treatment of initiation in adults and adolescents with infection by the Human Immunodeficiency Virus (HIV); however Dolutegravir (DTG) has a recent indication in the pediatric population. Objective: To describe the preliminary experience of pediatric patients with HIV infection in treatment with DTG. Method: A descriptive and prospective study was carried out in pediatric patients infected with HIV, in follow-up at JM de los Rios Children's Hospital (Caracas-Venezuela) from February to June 2019. Criteria for indication DTG, virological and immunological parameters were evaluated and appearance of adverse effects. For the analysis, the Access 2004 database and the Epi-Info 7 statistical program were used and the results were presented in frequency and percentage tables. Results: Of 193 patients, 56.5 % (n = 109) are adolescents and 9.2 % (n = 10) received DTG coformulate. 60 % belong to the male gender. A fashion of 15.6 years and an average weight of 40.75 kg were recorded as age. 50 % received DTG due to not having the previous ART scheme and only 10 % as the start of ART. 70 % did not present adverse effects, those presented were mild. Only 20 % of the patients had viral load and lymphocyte sub population prior to ART start without subsequent paraclinical control. Conclusions: The main indication for DTG was due to the resumption of antiretroviral therapy due to the lack of availability of the previous scheme. 70 % of the patients did not present adverse effects to the therapy.
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OBJECTIVE: To evaluate the prevalence of adverse drug reactions (ADR) and associated factors during the use of Highly Active Antiretroviral Therapy (HAART) in patients initiating treatment. METHODS: This is a cross-sectional analysis of a prospective study conducted in three public referral services specialized in HIV/AIDS care in Belo Horizonte, Brazil. Self-reported ADR and explanatory variables were obtained from face-to-face interview and from Information Systems. Associated factors with ADR were evaluated by logistic regression in SPSS software v.22. RESULTS: We included 399 patients, of which 85.5% reported at least one and 72.7% up to 5 ADRs after HAART initiation. Neurological reactions were the most frequent, with self-reported ADRs being distinct according to HAART regimen used. The global model showed higher chance of ADRs among females (OR = 3.52) and illicit drug users (OR = 2.28). Lower chance of ADRs was found for patients aged > 33 years (OR = 0.37), DTG/TDF/3TC users (OR = 0.41), and higher physical domain of quality of life (OR = 0.78). The model restricted to patients using the single-tablet regimen EFV/TDF/3TC showed lower ADRs among patients with CD4+ T lymphocyte count > 200 cells/mm3 (OR = 0.23) and higher independence domain of quality of life (OR = 0.74). The model restricted to DTG/TDF/3TC and to other regimens showed lower ADRs with higher physical domain of quality of life (OR = 0.74 and OR = 0.55, respectively). CONCLUSIONS: The prevalence of self-reported ADRs to first-line antiretroviral regimens was high and patients using DTG/TDF/3TC had a smaller number of ADRs. In addition to HAART regimen, sociodemographic, clinical, and quality of life characteristics were associated with ADRs.
Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Adolescente , Adulto , Idoso , Alcinos , Benzoxazinas/efeitos adversos , Brasil , Estudos Transversais , Ciclopropanos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Estudos Prospectivos , Piridonas , Qualidade de Vida , Inibidores da Transcriptase Reversa/administração & dosagem , Tenofovir/efeitos adversos , Adulto JovemRESUMO
os inibidores da integrase são a mais nova classe de antirretroviral aprovada, que agem impedindo a incorporação do DNA do HIV no genoma do linfócito T CD4+ (LTCD4+) do hospedeiro, limitando a propagação do vírus. o Dolutegravir e o inibidor da integrase mais moderno e como os demais inibidores apresenta de alta performance, boa tolerância; alta barreira genética para mutações de resistência, além de apresentar eficácia em pacientes já submetidos a tratamento antirretroviral anterior. Neste contexto o presente estudo trata-se de um estudo de revisão bibliográfica realizada de janeiro a junho de 2018, de artigos científicos de artigos científicos que abordam aspectos exclusivos do dolutegravir na terapia antirretroviral em comparação com outros esquemas terapêuticos. Concluindo que o tratamento com dolutegravir apresenta como principais vantagens à rápida supressão virológica; boa tolerância e alta barreira genética para mutações de resistência.
Integrase inhibitors are the newest class of approved antiretroviral drugs that act by preventing the incorporation of HIV DNA into the CD4 + T lymphocyte (LTCD4 +) genome of the host, limiting the spread of the virus. Dolutegravir and the most modern integrase inhibitor and like the other inhibitors presents high performance, good tolerance; high genetic barrier for resistance mutations, in addition to being effective in patients already submitted to previous antiretroviral treatment. In this context, the present study is a bibliographical review study conducted from January to June, 2018, of scientific papers on scientific articles dealing with exclusive aspects of dolutegravir in antiretroviral therapy compared to other therapeutic regimens. Concluding that dolutegravir treatment has the main advantages of rapid virological suppression; good tolerance and high genetic barrier for resistance mutations
Assuntos
HIV , Terapia Antirretroviral de Alta Atividade , Preparações Farmacêuticas , Síndrome da Imunodeficiência Adquirida , Inibidores de Integrase , Integrases , Carga Viral , AntirretroviraisRESUMO
INTRODUCTION: A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients. METHODS: PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm). RESULTS: Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686-36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296-517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm3 (IQR: 180-462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV-naive patients. CONCLUSIONS: This novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV-therapy-naive patients. CLINICALTRIALS.GOV IDENTIFIER: NCT02211482.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Lamivudina/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Quimioterapia Combinada , Feminino , HIV-1/genética , Humanos , Masculino , Oxazinas , Projetos Piloto , Piperazinas , Piridonas , Carga ViralRESUMO
Dolutegravir (DTG) es un inhibidor de la integrasa del VIH aprobado recientemente como tratamiento por la FDA (Food and Drug Administration) en los Estados Unidos. Utilizado como parte de un tratamiento de primera línea, DTG es el único tratamiento antirre-troviral frente al cual no se ha seleccionado resistencia en la clínica. Nuestra teoría es que esto se debe al prolongado tiempo de unión del DTG a la enzima integrasa así como a una capacidad de replicación muy disminuida por parte de los virus que podrían volverse resisten-tes al DTG. Además, conjeturamos que DTG podría ser utilizado en estrategias que apunten a la erradicación del VIH
Dolutegravir (DTG)is an HIV integrase inhibitor that was recently approved for therapy by the Food and Drug Administration in the United States.When used as part of first-line therapy,DTG is the only HIV drug that has not selected for resistance mutations in the clinic. We believe that this is due to the long binding time of DTG to the integrase enzyme as well as greatly diminished replication capacity on the part of viruses that might become resistant to DTG.We further speculatethat DTG might be able to be used in strategies aimed at HIV eradication