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INTRODUCTION: Abacavir is among the first-line initial antiretroviral regimens for most patients living with HIV/AIDS (PLWHA). Although well tolerated, it is associated with hypersensitivity reaction (HSR), which is treatment-limiting and potentially life-threatening. HSR was shown to be associated with the class I MHC allele, HLA-B*57:01. In this study, we aimed to evaluate the prevalence of HLA-B*57:01 in PLWHA in Istanbul, Türkiye. MATERIAL AND METHODS: Five HIV treatment centers in Istanbul included all sequential treatment-- naïve, ≥ 18 years adult PLWHA, between December 2017- December 2021. Demographic, clinical, and laboratory data were collected at baseline and during treatment. HLA-B* 57:01 genotyping was determined with PCR-SSP. RESULTS: Eight hundred sixty-seven PLWHA were included (male:91%, mean age 39.6±11.1 years). 1.6% of patients were found to be HLA-B*57:01 positive. Among HLA-B*57:01 positive patients, 4 were initially given abacavir-containing treatment; they were switched to non-abacavir treatment upon the allele found to be positive. CONCLUSION: Although previous studies reported the HLA-B*57:01 prevalence of PLWHA in Türkiye as 3-3.6%, we have found the prevalence to be 1.6%. The current study includes higher numbers of patients than the previous studies. Furthermore, patients from all over the country apply to the centers in Istanbul; compared to the other studies, which involve patients limited to the relevant regions, it can be assumed that the number in our cohort is more representative of the country. In conclusion, the prevalence of the HLA-B*57:01 allele in PLWHA in this study is relatively low. With evident benefit in preventing abacavir HSR, HLA-B*57:01 should be screened in planning antiretroviral therapy.
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BACKGROUND: Antiretroviral drugs in people living with HIV-1 (PLHIV-1) often trigger side effects which may lead to discontinuation or failure of treatment. Human Leukocyte Antigen B*57:01 (HLA-B*57:01) allele is known to predict hypersensitivity reactions to Abacavir. Very few data are available on the prevalence of HLA-B*57:01 allele in PLHIV-1 in African countries. This study aimed to screen for HLA-B*57:01 allele in PLHIV-1 in Benin. METHODS: This pilot study was carried out on one hundred ten PLHIV-1 enrolled in two health facilities in Benin. Socio-demographic and clinical data were collected. Biological data were determined and HLA-B*57:01 allele was genotyped, using Single Specific Primer-Polymerase Chain Reaction in blood samples. RESULTS: 70% of participants were female. PLHIV-1 were under TDF + 3TC + DTG (47.2%) or TDF + 3TC + EFV (57.3%). Their median age was 41 [36-48.75] years and the average CD4 + T cell count was 249 [130-381.25] cells/µl. The average viral load in treatment failure PLHIV-1 was 4.7 [3.9-5.2] Log10. At the inclusion date, twenty-nine (26.4%) PLHIV-1 under TDF + 3TC + EFV have developed hypersensitivity reactions. None of 110 patients had shown HLA-B*5701 allele. CONCLUSION: Our study revealed that HLA-B*57:01 allele was very rare in PLHIV-1 in Benin, suggesting that its screening before starting the Abacavir regimen did not seem necessary.
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Hipersensibilidade a Drogas , Infecções por HIV , HIV-1 , Antígenos HLA-B , Humanos , Projetos Piloto , Feminino , Masculino , Benin , Adulto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/imunologia , Antígenos HLA-B/genética , Hipersensibilidade a Drogas/genética , Hipersensibilidade a Drogas/imunologia , Pessoa de Meia-Idade , HIV-1/genética , HIV-1/imunologia , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Alelos , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/uso terapêutico , Ciclopropanos , Didesoxiadenosina/análogos & derivadosRESUMO
INTRODUCTION: Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC) have been approved in the US for adults and children with HIV weighing ≥ 6 kg. This analysis assessed the ability of previously developed ABC, DTG, and 3TC pediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using dispersible tablet (DT) and tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study. METHODS: IMPAACT 2019 was a Phase I/II study assessing the PK, safety, tolerability, and efficacy of ABC/DTG/3TC FDC in children with HIV-1. Intensive and sparse PK samples were collected over 48 weeks. Existing drug-specific pediatric PopPK models for ABC (2-compartment), DTG (1-compartment), and 3TC (1-compartment) were applied to the IMPAACT 2019 drug concentration data without re-estimation (external validation) of PopPK parameters. Drug exposures were then simulated across World Health Organization weight bands for children weighing ≥ 6 to < 40 kg for each drug and compared with pre-defined exposure target ranges. RESULTS: Goodness-of-fit and visual predictive check plots demonstrated that the previously developed pediatric PopPK models sufficiently described and predicted the data. Thus, new PopPK models describing the IMPAACT 2019 data were unnecessary. Across weight bands, the predicted geometric mean (GM) for ABC AUC0-24 ranged from 14.89 to 18.50 µg*h/ml, DTG C24 ranged from 0.74 to 0.95 µg/ml, and 3TC AUC0-24 ranged from 10.50 to 13.20 µg*h/ml. These exposures were well within the pre-defined target ranges set for each drug. CONCLUSION: This model-based approach leveraged existing pediatric data and models to confirm dosing of ABC/DTG/3TC FDC formulations in children with HIV-1. This analysis supports ABC/DTG/3TC FDC dosing in children weighing ≥ 6 kg.
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Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM.
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Bone mineral density (BMD) loss in people living with HIV occurs with the initiation of combined antiretroviral therapy (cART), particularly with tenofovir disoproxil fumarate (TDF) containing cART. Switching from TDF to abacavir (ABC) or dolutegravir (DTG) leads to increased BMD. Whether BMD gains are due to cessation of TDF or anabolic effects of ABC or DTG is unclear. We investigated the effects of ABC and DTG on osteoblast lineage cells in vitro and in vivo. Primary human osteoblasts and male C57BL/6 mice were treated with individual antiretrovirals (ARVs) or a combination of ABC/DTG/lamivudine (3TC). Nearly all ARVs and cART inhibited osteogenic activity in vitro. Due to the importance of Wnt/ß-catenin in bone formation, we further investigated ARV effects on the Wnt/ß-catenin pathway. ABC, alone and as part of ABC/DTG/3TC, increased osteoblastic ß-catenin activity as indicated by increased TOPFlash activity, hypo-phosphorylated (active) ß-catenin staining, and ß-catenin targeted gene expression. Mice treated with TDF had decreased lumbar spine BMD and trabecular connectivity density in the vertebrae, while those treated with ABC/DTG/3TC reduced cortical area and thickness in the femur. Mice treated with ABC alone had no bone structural changes, increased circulating levels of the bone formation marker, P1NP, and elevated expression of the Wnt/ß-catenin target gene, Lef1, in osteocyte enriched samples. Further, bones from ARV-treated mice were isolated to evaluate ARV distribution. All ARVs were detected in the bone tissue, which was inclusive of bone marrow, but when bone marrow was removed, only TDF, ABC, and DTG were detected at ~0.1% of the circulating levels. Overall, our findings demonstrate that ABC activates Wnt/ß-catenin signaling, but whether this leads to increased bone formation requires further study. Assessing the impact of ARVs on bone is critical to informing ARV selection and/or discovery of regimens that do not negatively impact the skeleton.
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Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity (AHS), which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as interferon-γ, interleukin-1ß, and CCL27, and induced T lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate (4-PB). HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-PB. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated AHS. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions.
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El alelo HLA B*57:01 es un marcador genético asociado con la hipersensibilidad al fármaco anti-retroviral abacavir (ABC) y su frecuencia en la población peruana todavía es desconocida. El objetivo fue identificar el alelo HLA B*57:01 en una población militar de Lima, Perú. Se reclutaron 43 personas viviendo con VIH (PVV) quienes aceptaron participar a través de un consentimiento informado. La detección del alelo HLA B*57:01 se realizó mediante RPC en tiempo real (RT-PCR). Asimismo, se determinó la carga viral (CV), el recuento de linfocitos CD4 y la genotipificación del VIH. Se identificaron dos casos positivos al alelo HLA B*57:01 (4,7%). Además, uno de ellos presentó múltiples mutaciones de resistencia a los anti-retrovirales (ARV), incluyendo ABC. Se demostró por primera vez en el Perú la presencia del alelo HLA B*57:01.
The HLA B*57:01 allele is a genetic marker associated with hypersensitivity to the antiretroviral Abacavir (ABC) and its frequency in the Peruvian population is still unknown. The objective was to identify the HLA B*57:01 allele in a military population from Lima, Peru. Forty three people living with HIV (PLWH) were recruited, who agreed to participate through informed consent. Detection of the HLA B*57:01 allele was performed by real-time PCR (RT-PCR). Likewise, viral load (VL), CD4 lymphocyte count and HIV genotyping were determined. Two cases positive for the HLA B*57:01 allele (4.7%) were identified. In addition, one of them had multiple resistance mutations to antiretrovirals (ARVs), including ABC. The presence of the HLA B*57:01 allele was demonstrated for the first time in Peru.
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Humanos , Masculino , Pessoa de Meia-Idade , Infecções por HIV/genética , Fármacos Anti-HIV/efeitos adversos , Hipersensibilidade a Drogas/genética , Militares , Peru , Antígenos HLA-B/genética , Marcadores Genéticos , Infecções por HIV/tratamento farmacológico , HIV/genética , Contagem de Linfócito CD4 , Carga Viral/genética , Predisposição Genética para Doença , Ciclopropanos/efeitos adversos , Hipersensibilidade a Drogas/imunologia , Alelos , Reação em Cadeia da Polimerase em Tempo Real , GenótipoRESUMO
Several patients with cutaneous adverse drug reactions exhibit extracutaneous organ damages, and it becomes severe in a few patients resulting in death due to multiorgan failure. Understanding the sequential changes in various organs in patients with cutaneous eruption following drug administration will help understand disease onset and progression, aiding the development of prevention strategies and interventions. Therefore, we aimed to understand the effects of abacavir (ABC) on various organs in patients with ABC-induced eruptions by evaluating its effects in a mouse model. We found pathological changes in various organs of HLA-B*57:01 transgenic mice (B*57:01-Tg) following oral administration of ABC (20 mg/body/day). B*57:01-Tg exhibited a significant body weight decrease from day 1 of ABC administration, and reddening of the auricle was observed from day 5, and approximately 2/3 mice died by day 7. Histopathological examination revealed severe thymic atrophy after day 3, infiltration of inflammatory cells, predominantly lymphocytes with neutrophils, not only in the skin but also in the liver, kidney, and lung after day 5, and an increased number of lymphocytes with enlarged nuclei and granulocytic hematopoiesis were observed in the spleen after day 5. Blood chemistry revealed that albumin/globulin ratio was below 1.0 on day 5, reflecting a systemic inflammatory response, and the aspartate aminotransferase concentration rose to 193 ± 93.0 U/L on day 7, suggesting that cell damage may have occurred in various organs including liver accompanying inflammatory cell infiltration. These examinations of a mouse model of ABC-induced skin eruption show that disorders in various organs other than the skin should be considered and provide insights into the unexpected early systemic responses dependent on HLA-B*57:01. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00220-1.
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Herein, two different sustainable and green signal processing spectrophotometric approaches, namely, derivative spectroscopy and wavelet transform, have been utilized for effective measurement of the antiretroviral therapy abacavir and lamivudine in their pharmaceutical formulations. These methods were used to enhance the spectral data and differentiate between the absorption bands of abacavir and lamivudine in order to accurately measure their concentrations. For determining abacavir and lamivudine, the first derivative spectrophotometric method has been applied to the zero-order and ratio spectra of both drugs. The same approach has been tested using the continuous wavelet transform method where a second order 2.4 of rbio and bior wavelet families were found to be optimum for measuring both drugs. Validation of the proposed methods affirmed their reliability in terms of linearity over the concentration range 1.5-30 µg/mL and 1.5-36 µg/mL for abacavir and lamivudine, respectively, precision (RSD < 2 %), and accuracy with mean recoveries ranging between 98 % and 102 %. Additionally, these spectrophotometric methodologies were applied to real pharmaceutical preparations and yielded results congruent with a prior chromatographic method. Most prominently, the proposed methods stood out for their greenness and sustainability with 97 points as evaluated by the analytical eco-scale method and a score value of 0.79 as analyzed by AGREE method, thereby making them suitable for resource-limited settings and highlighting the potential for broader application of green analytical methods in pharmaceutical analysis.
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Ciclopropanos , Didesoxiadenosina/análogos & derivados , Lamivudina , Análise de Ondaletas , Humanos , Lamivudina/química , Reprodutibilidade dos Testes , Espectrofotometria , Preparações FarmacêuticasRESUMO
Introduction Human immunodeficiency virus (HIV) incidence and prevalence are increasing in Saudi Arabia, with a total prevalence of 12,000 in 2020. Treatment of HIV patients includes multiple regimens that may involve abacavir (ABC), which is a potent drug for treating HIV and can be used as a single or combined pill. Unfortunately, its use was limited by the known associated hypersensitivity reaction (HSR). A worldwide literature review over the past decades reported that the incidence of ABC-related HSR is 5-8%. Methods The study was a cross-sectional multicentric study involving five governmental hospitals in Saudi Arabia and included all HIV patients who were following in these centers. Results Out of 3082 patients, 1293 were tested for HLA-B*5701. The prevalence for ABC-HSR is 1.59%, with variability among the five hospitals, with the highest in King Fahad Hospital in Hafuf (KFH-H) at 4.00% and the lowest in Dammam Medical Complex (DMC) at 0.49%. In previous studies, HLA-B*5701 associated with ABC-HSR varied among different ethnic groups. Our study showed that two patients developed ABC-HSR clinically while they were both negative for HLA-B*5701. Conclusion The fact that patients with negative genetic testing are still at risk of developing ABC-HSR makes continuing screening for HLA-B*5701 status essential, as the consequences of missing such a life-threatening HSR could be detrimental.
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BACKGROUND: The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands. METHODS: Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0-24) of 6.4-50.4 mg h/L were used as targets. RESULTS: Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0-24.9 kg, but children weighing 3-5.9 kg were predicted to be overexposed. CONCLUSIONS: Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3-5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.
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Fármacos Anti-HIV , Infecções por HIV , Adulto , Criança , Humanos , Lactente , Infecções por HIV/tratamento farmacológico , Didesoxinucleosídeos/uso terapêutico , Uganda , QuêniaRESUMO
Background: Abacavir (ABC) in combination with other antiretroviral drugs, is used to treat people living with HIV (PLWH). However, it is linked to a fatal hypersensitivity reaction in susceptible individuals, and is strongly associated with the HLA-B*57:01 allele. Materials & methods: A total of 152 patients, 50 PLWH and 102 HIV-1 negative patients, were assessed for the HLA-B*57:01 allele through a sequence-specific primer PCR. Results: All PLWH tested negative for the HLA-B*57:01 allele, but two HIV-negative patients were found to have HLA-B*57, with one of them expressing the HLA-B*57:01 allele. Conclusion: Given the low prevalence of this risk allele in the population, testing for the presence of HLA-B*57:01 in PLWH may not provide significant benefit for the reported population.
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OBJECTIVES: The aim of our study is to reveal the prevalence of HLA-B*57 in the Turkish population and to provide new perspectives to physicians starting abacavir therapy in HIV patients. BACKGROUND: Abacavir, one of the drugs used to treat HIV infection, can cause hypersensitivity reactions in some patients. These hypersensitivity reactions have been shown to be associated with the HLA-B*57:01 allele. High-resolution HLA-B*57:01 scanning has a time and cost disadvantage compared with low-resolution HLA-B*57 scanning. Before starting abacavir treatment, we will discuss whether high-resolution scanning is more beneficial in individuals who are positive on HLAB* 57 screening. This is the study with the largest cohort to investigate the prevalence of HLA-B*57 in Turkey. METHODS: The results of 25 thousand 318 people who applied to Bursa Uludag University Faculty of Medicine, Department of Immunology for HLA-B* typing were scanned. RESULTS: In our study, the HLA-B*57 serotype was detected in 827 (3.3%) individuals. CONCLUSION: Considering these results, it can be assumed that the prevalence of HLA-B*57:01 in Turkey is lower than 3.3%. Instead of a high-resolution HLA-B*57:01 scan in all patients starting abacavir therapy, a high-resolution HLA-B*57:01 scan might be of greater benefit in patients who are positive on a low-resolution HLA-B*57 scan.
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Fármacos Anti-HIV , Hipersensibilidade a Drogas , Infecções por HIV , Humanos , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/epidemiologia , Prevalência , Turquia/epidemiologia , Sorogrupo , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/genética , Hipersensibilidade a Drogas/tratamento farmacológico , Antígenos HLA-B/genética , Didesoxinucleosídeos/efeitos adversosRESUMO
BACKGROUND: Varicella-Zoster virus (VZV) vasculopathy occasionally occurs in immunocompromised patients and is difficult to treat. The risk factor and optimal therapy remain unclear. Patients with human immunodeficiency virus (HIV) and dysphagia or difficulty in oral intake receive antiretroviral therapy (ART) suspension. However, there remains little evidence regarding ART suspension. CASE PRESENTATION: We experienced a case of a 55-year-old man diagnosed with HIV and severe multiple cerebral infarctions due to VZV vasculopathy. We started on bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) and acyclovir (ACV), and prednisone. He was started on BIC/TAF/FTC suspension because of deteriorated swallowing. The HIV viral load was increased; however, no drug-resistance genes were detected. We successfully treated him with doltegravir/abacavir/lamibudine suspension. We performed two literature reviews of the administration of BIC/TAF/3TC suspension and VZV vasculopathy in patients with HIV. Three cases of BIC/TAF/3TC suspension were considered treatment failures. Recent history of VZV infection and a CD4 count under 200 µL may be risk factors for VZV vasculopathy. The effective treatment may be using steroid and ACV; however, treatment duration could differ. CONCLUSIONS: BIC/TAF/FTC suspension administration may be unstable, and treating ACV and steroid may be optimal therapy for VZV vasculopathy; however, the evidence level is low.
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Fármacos Anti-HIV , Infecções por HIV , Masculino , Humanos , Pessoa de Meia-Idade , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Herpesvirus Humano 3 , Carga Viral , Tenofovir/uso terapêutico , Tenofovir/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Emtricitabina/uso terapêutico , Emtricitabina/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Combinação de Medicamentos , HIV , Infarto Cerebral/induzido quimicamente , Infarto Cerebral/tratamento farmacológicoRESUMO
Anti-human immunodeficiency virus (HIV) drug abacavir (ABC) binds to the specific allele of human leukocyte antigen (HLA-B*57:01) and activates CD8+ T cells by presenting altered abnormal peptides. Here, we examined the effect of ABC-induced altered self-presentation by HLA-B*57:01 on immunogenicity of cancer cells and CD8+ T-cell-dependent anti-tumor immunity. We established human-mouse chimeric HLA-B*57:01-expressing tumor cell lines (B16F10 and 3LL) and tested the anti-tumor effect of ABC in vivo. ABC treatment inhibited the growth of HLA-B*57:01-expressing tumors by a CD8+ T-cell-dependent mechanism. ABC treatment induced CXCR3-dependent infiltration of CD8+ T cells into HLA-B*57:01-expressing tumors, and activated those tumor-infiltrating CD8+ T cells to proliferate and secrete IFN-γ. The activation of CD8+ T cells using drug-induced altered self-presentation may be a new strategy to increase tumor immunogenicity and improve the efficacy of immunotherapy.
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Antígenos de Neoplasias , Linfócitos T CD8-Positivos , Camundongos , Animais , Linhagem Celular Tumoral , ImunoterapiaRESUMO
BACKGROUND: Abacavir/dolutegravir/lamivudine has been indicated in Korea since 2015 for treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination. This regulatory post-marketing surveillance (PMS) study evaluated the real-life safety and effectiveness of abacavir/dolutegravir/lamivudine in patients with HIV-1 in clinical practice in Korea. MATERIALS AND METHODS: This open-label post-marketing surveillance examined data from consecutive patients (aged ≥12 years) with HIV-1 infection receiving abacavir/dolutegravir/lamivudine according to locally approved prescribing information; treatment-naïve and treatment-experienced patients were permitted. Data regarding patient demographics, medical history, clinical characteristics, medications (HIV-1 related and concomitant), resource utilization and comorbidities were extracted from patient records over a 1-year treatment period. Outcomes included safety of abacavir/dolutegravir/lamivudine (primary endpoint) and real-life effectiveness according to physician's global assessment and the proportion of patients with plasma HIV-1 RNA count <50 copies/mL at 48 weeks. RESULTS: Of 663 patients treated with abacavir/dolutegravir/lamivudine at 27 centers in Korea (June 2015 - June 2021), 656 were eligible for the safety analyses and 484 for effectiveness analyses. Patients were mostly male (94.8%) mean age was 42.2 ± 14.0 years and mean weight was 68.1 ± 11.0 kg. Adverse events (AEs, n = 656 in total) were mostly mild in severity, with the most common being nasopharyngitis (7.9%), retching (7.5%), headache (4.9%). Of 121 adverse drug reactions (ADRs), the most frequent were retching (4.4%), headache (1.8%) and dizziness (1.7%). Of 55 serious AEs, the most frequent were anogenital warts (1.1%). Of 2 serious ADRs, nothing was unexpected, and both resolved. The risk of experiencing an AE while receiving abacavir/dolutegravir/lamivudine appeared to be especially increased in patients receiving concomitant medications for other conditions. Abacavir/dolutegravir/lamivudine effectively suppressed HIV-1 (96.1% of patients had plasma HIV-1 RNA <50 copies/mL), and 99.0% of patients showed symptom improvement based on physician assessment. CONCLUSION: Results of this PMS study showed that abacavir/dolutegravir/lamivudine administered as highly active antiretroviral therapy was well tolerated and effective in patients with HIV-1 infection.
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There is ongoing debate as to whether abacavir (ABC) increases the risk for cardiovascular disease(CVD) in people living with HIV (PLHIV) and the mechanisms underlying this possible association. We recently showed that the use of an ABC-containing regimen was independently associated with increased thrombin generation (TG). In the present study, we aim to explore these findings further, by studying the mechanistical processes that underly the global thrombin generation test via thrombin dynamics analysis. Thrombin dynamics analysis can pinpoint the cause of increased thrombin generation associated with ABC-use either to the procoagulant prothrombin conversion pathway or the anticoagulant thrombin inactivation pathway. In this cross-sectional study, 208 virally suppressed PLHIV were included, of whom 94 were on a ABC-containing regimen, 92 on a tenofovir disoproxil fumarate (TDF)-containing regimen, and the remainder on other regimens. We used Calibrated Automated Thrombinography to measure thrombin generation and perform thrombin dynamics analysis. The total amount of prothrombin conversion, as well as the maximum rate of prothrombin conversion were significantly increased in PLHIV on an ABC containing regimen compared to other treatment regimens. The levels of pro- and anticoagulant factors were comparable, indicating that the ABC-induced changes affect the kinetics of prothrombin conversion rather than procoagulant factor levels. Moreover, Von Willebrand Factor (VWF), active VWF and VWF pro-peptide levels were significantly higher in PLHIV than controls without HIV. However, they did not differ between ABC and non-ABC treated participants.
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Infecções por HIV , Protrombina , Humanos , Trombina/metabolismo , Fator de von Willebrand , Estudos Transversais , AnticoagulantesRESUMO
BACKGROUND: WHO guidelines recommend abacavir in first-line antiretroviral treatment for children and neonates. However, there is no approved dose <3 months of age, and data in neonates are limited. METHODS: We included infants who initiated ART aged <3 months, between 2006 and 2019, in nine South African cohorts. In those who received abacavir or zidovudine, we described antiretroviral discontinuation rates; and 6- and 12-month viral suppression (<400 copies/mL). We compared infants aged <28 and ≥28 days, those weighing <3 and ≥3 kg. RESULTS: Overall 837/1643 infants (51%) received abacavir and 443 (27%) received zidovudine. Median (interquartile range, IQR) age was 52 days (23-71), CD4 percentage was 27.9 (19.2-38.0), and weight was 4.0 kg (3.0-4.7) at ART initiation. In those with ≥1 month's follow-up, 100/718 (14%) infants discontinued abacavir, at a median of 17.5 months (IQR 6.5-39.5). Abacavir discontinuations did not differ by age or weight category (p = 0.4 and 0.2, respectively); and were less frequent than zidovudine discontinuations (adjusted hazard ratio 0.14, 95% confidence interval 0.10-0.20). Viral suppression at 12 months occurred in 43/79 (54%) and 130/250 (52%) of those who started abacavir aged <28 and ≥28 days, respectively (p = 0.8); 11/19 (58%) and 31/60 (52%) in those who weighed <3 and ≥3 kg, respectively (p = 0.6); and 174/329 (53%) in those on abacavir versus 77/138 (56%) in those on zidovudine (adjusted odds ratio 1.8, 95% confidence interval 1.0-3.2). CONCLUSION: Our data suggest that abacavir may be used safely in infants <28 days old or who weigh <3 kg.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Criança , Recém-Nascido , Lactente , Humanos , Zidovudina/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , África do Sul/epidemiologia , Didesoxinucleosídeos/efeitos adversos , Antirretrovirais/uso terapêutico , Carga ViralRESUMO
A novel electrochemical approach using two different electrode materials, platinum and boron-doped diamond (BDD), was employed to study the oxidative stability of the drug abacavir. Abacavir samples were subjected to oxidation and subsequently analysed using chromatography with mass detection. The type and amount of degradation products were evaluated, and results were compared with traditional chemical oxidation using 3% hydrogen peroxide. The effect of pH on the rate of degradation and the formation of degradation products were also investigated. In general, both approaches led to the same two degradation products, identified using mass spectrometry, and characterised by 319.20 and m/z 247.19. Similar results were obtained on a large-surface platinum electrode at a potential of +1.15 V and a BDD disc electrode at +4.0 V. Degradation of 20% of abacavir, the rate required for pharmaceutical stability studies, took only a few minutes compared to hours required for oxidation with hydrogen peroxide. Measurements further showed that electrochemical oxidation in ammonium acetate on both types of electrodes is strongly pHdependent. The fastest oxidation was achieved at pH 9. The pH also affects the composition of the products, which are formed in different proportions depending on the pH of the electrolyte.
RESUMO
This study explores the photocatalytic transformation of the antiviral drug abacavir employing different advanced oxidation processes (AOPs) such as UV/TiO2, UV/MOF/H2O2, UV/MOF/S2O82-, UV/Fe2+/H2O2, and UV/Fe2+/S2O82-. All processes appear to be effective in eliminating abacavir within a few minutes, while the evolution profile of the basic transformation product, descyclopropyl-abacavir (TP-247) was also monitored. Moreover, the implementation of the most efficient technologies towards the removal of abacavir in different matrices such as wastewater effluent and leachate was also assessed, revealing that the organic matter present or the inorganic constituents can retard the whole process. Four major transformation products were detected, and their time-evolution profiles were recorded in all studied matrices, revealing that different transformation pathways dominate in each matrix. Finally, the prediction of the toxicity of the major TPs employing ECOSAR software was conducted and showed that only hydroxylation can play a detoxification role in the treated solution.