RESUMEN
PURPOSE: The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma (OSCC). This study aims to evaluate the association of CCL5 and CCR5 with the behavior of oral cancer and assess the therapeutic potential of a CCR5 antagonist. METHODS: A retrospective study to analyze CCR5 and CCL5 expression on paraffin-embedded tissues was performed. In cell lines, rhCCL5 was added to induce CCR5-related pathways, and Maraviroc and shRNA against CCR5 were used to neutralize the receptor. Finally, an in vivo murine orthotopic xenograft model of tongue cancer was used to evaluate Maraviroc as an oncologic therapy. After 15 days, the mice were killed, and the primary tumors and cervical lymph nodes were analyzed. RESULTS: The expression of CCR5 was associated with clinical stage and metastasis, and CCL5 was related to overall survival. Adding rhCCL5 induced cell proliferation, while shRNA and Maraviroc reduced it in a dose-dependent manner. Maraviroc treatment also increased apoptosis and modified cytoskeletal organization. In vivo, Maraviroc reduced neck metastasis. CONCLUSIONS: The effects of CCR5 antagonists in OSCC have been poorly studied, and this study reports in vitro and in vivo evidence for the effects of Maraviroc in OSCC. Our results suggest that the CCR5/CCL5 axis plays a role in oral cancer behavior, and that its inhibition is a promising new therapy alternative.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Animales , Ratones , Maraviroc/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello , Estudios Retrospectivos , Línea Celular Tumoral , Neoplasias de la Boca/tratamiento farmacológico , ARN Interferente Pequeño/metabolismo , Microambiente Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismoRESUMEN
CC Chemokine receptor 5 (CCR5), a member of the Superfamily of G Protein-Coupled Receptors (GPCRs), is an important effector in multiple physiopathological processes such as inflammatory and infectious entities, including central nervous system neuroinflammatory diseases such as Alzheimer's disease, recovery from nervous injuries, and in the HIV-AIDS infective processes. Thus, CCR5 is an attractive target for pharmacological modulation. Since maraviroc was described as a CCR5 ligand that modifies the HIV-AIDS progression, multiple efforts have been developed to describe the functionality of the receptor. In this work, we characterized key structural features of the CCR5 receptor employing extensive atomistic molecular dynamics (MD) in its apo form and in complex with an endogenous agonist, the chemokine CCL5/RANTES, an HIV entry inhibitor, the partial inverse agonist maraviroc, and the experimental antagonists Compound 21 and 34, aiming to elucidate the structural features and mechanistic processes that constitute its functional states, contributing with structural details and a general understanding of this relevant system.
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Inhibidores de Fusión de VIH , Infecciones por VIH , Antagonistas de los Receptores CCR5/farmacología , Antagonistas de los Receptores CCR5/uso terapéutico , Quimiocina CCL5/farmacología , Infecciones por VIH/tratamiento farmacológico , Humanos , Imidazoles , Ligandos , Maraviroc/uso terapéutico , Receptores CCR5 , Sulfonamidas , TiofenosRESUMEN
INTRODUCTION: Unlike most high-income countries where subtype B viruses predominate, the Cuban HIV-1 epidemic is characterized by a great diversity of subtypes and circulating recombinant forms. Some studies have shown that HIV variants exhibiting a preference for the CXCR4 co-receptor (X4-tropic) could have impacts on disease pathogenesis, with clinical implications for antiviral treatment plans. Determination of HIV co-receptor tropism is crucial for clinicians in deciding whether maraviroc is an appropriate antiviral. OBJECTIVE: Characterize V3 sequence variability and its relation to viral tropism across different subtypes circulating in Cuba and explore how this may affect treatment success with maraviroc. METHODS: We designed a cross-sectional study that included 72 plasma samples obtained at the Pedro Kourí Tropical Medicine Institute in Havana, Cuba. We sequenced the C2V3 env region and assessed subtype based both on env and pol sequences; tropism was predicted by Geno2pheno analysis. Additionally, 35 V3-loop Cuban sequences, obtained from a previous study, were incorporated into the analysis. Statistical associations among virological, clinical and epidemiological variables were assessed by a chi-square test. RESULTS: Tropism prediction for 72 variants revealed that CRF19_cpx was associated with dual-tropic R5X4 viruses (p = 0.034). Moreover, when 35 sequences from a former study were added, the association was significant not only for R5X4 (p = 0.019) but also for X4-tropic variants (p = 0.044). Alignment of 107 V3-loop sequences showed wide diversity among the different HIV-1 subtypes circulating in Cuba. CONCLUSIONS: In accordance with G2P, CRF19_cpx is a genetic variant with a high proportion of X4 and R5X4-tropic viruses. The results from the present study suggest that the Cuban recombinant could be a more pathogenic variant and that maraviroc may not be suitable for patients infected with CRF19_cpx.
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Infecciones por VIH , VIH-1 , Estudios Transversales , Cuba/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH-1/genética , Humanos , Maraviroc , TropismoRESUMEN
Asian macaques infected with simian immunodeficiency viruses (SIVs) isolated from African non-human primates develop a disease similar to human AIDS. SIV enters its target cells by binding to CD4 and a coreceptor, typically CCR5. Maraviroc is an entry inhibitor of human immunodeficiency virus type 1 (HIV-1) that prevents the interaction between CCR5 and the surface subunit gp120 of the viral envelope glycoprotein (Env). Thus far, the activity of maraviroc on SIV entry has been poorly studied. Here, we determined in vitro pharmacological parameters of the effect of maraviroc on the SIV Env association with CCR5. Cell-to-cell fusion inhibition assays were used to compare the susceptibility to maraviroc of the SIVsmmPBj Env-CCR5 interaction with that of HIV-1BaL Env. Analysis of dose-response curves and determination of IC50 values demonstrate that increasing concentrations of maraviroc inhibit the membrane fusion activity of SIVsmmPBj Env in a manner and to an extent similar to that of HIV-1BaL Env.
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Antagonistas de los Receptores CCR5/farmacología , Inhibidores de Fusión de VIH/farmacología , Maraviroc/farmacología , Receptores CCR5/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Proteínas del Envoltorio Viral/metabolismo , Animales , Células HEK293 , Humanos , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Envoltura Viral/metabolismo , Internalización del Virus/efectos de los fármacosRESUMEN
Antiretroviral therapy (ART) is typically composed of a combination of three antiretroviral drugs and is the treatment of choice for people with human immunodeficiency virus type 1/acquired immune deficiency syndrome (HIV-1/AIDS). However, it is unable to impact on viral reservoirs, which harbour latent HIV-1 genomes that are able to reignite the infection upon treatment suspension. The aim of this study was to provide an estimate of the safety of the disease-modifying antirheumatic agent auranofin and its impact on the HIV-1 reservoir in humans under intensified ART. For this purpose, an interim analysis was conducted of three of the six arms of the NCT02961829 clinical trial (five patients each) with: no intervention, i.e. continuation of first-line ART; intensified ART (ARTâ¯+â¯dolutegravir and maraviroc); and intensified ART plus auranofin. Auranofin treatment was found to be well tolerated. No major adverse events were detected apart from a transient decrease in CD4+ T-cell counts at Weeks 8 and 12. Auranofin decreased total viral DNA in peripheral blood mononuclear cells compared with ART-only regimens at Week 20 (Pâ¯=â¯0.036) and induced a decrease in integrated viral DNA as quantified by Alu PCR. Despite the limited number of patient-derived sequences available in this study, phylogenetic analyses of nef sequences support the idea that auranofin may impact on the viral reservoir. [ClinicalTrials.gov ID: NCT02961829].
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Antirreumáticos/uso terapéutico , Auranofina/uso terapéutico , VIH-1/genética , Provirus/efectos de los fármacos , Provirus/genética , Latencia del Virus/efectos de los fármacos , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , ADN Viral/efectos de los fármacos , ADN Viral/genética , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Maraviroc/uso terapéutico , Oxazinas , Piperazinas , PiridonasRESUMEN
BACKGROUND: Maraviroc is a CC-chemokine receptor 5 antagonist approved to treat adults infected with CC-chemokine receptor 5-tropic (R5) HIV-1. Study A4001031 was conducted to evaluate the pharmacokinetics, safety and efficacy of maraviroc in combination with optimized background therapy in treatment-experienced pediatric patients infected with R5 HIV-1 and support registration of maraviroc for pediatric use. METHODS: This is an open-label, 2-stage, age-stratified, noncomparative multicenter study. One-hundred and three participants were enrolled into 4 age/formulation cohorts and dosed twice daily. Initial doses were determined by body surface area and optimized background therapy, based on drug interactions with maraviroc in adults. Dose adjustment and pharmacokinetic reevaluation occurred if the average concentrations (Cavg) at Week 2 were <100 ng/mL (Stage 1-dose finding). RESULTS: Data from the Week 48 analysis demonstrated that 49/50 Stage 1 participants rolling over into Stage 2 (safety and efficacy) achieved Cavg ≥100 ng/mL. Doses were identified that achieved similar concentration ranges to those seen in adults. The majority (90/103) received optimized background therapy containing potent cytochrome P450 3A inhibitors. Maraviroc was well tolerated and the safety and efficacy were comparable to those of adults. All cohorts had a mean decrease from baseline in HIV-1 RNA of >1 log10. Increases from baseline in the median CD4+ cell count and percentage were seen for all age groups. CONCLUSIONS: The maraviroc dosing strategy resulted in participants achieving the target Cavg, with exposure ranges similar to those observed in adults on approved doses. The safety and efficacy of maraviroc in this pediatric population were comparable to those seen in adults
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Humanos , Niño , VIH-1/efectos de los fármacos , Maraviroc/farmacocinéticaRESUMEN
Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/µl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.
Asunto(s)
Antagonistas de los Receptores CCR5 , Ciclohexanos/efectos adversos , Ciclohexanos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Triazoles/efectos adversos , Triazoles/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Brasil , Recuento de Linfocito CD4 , Darunavir , Quimioterapia Combinada , Femenino , Inhibidores de Fusión de VIH/efectos adversos , Inhibidores de Fusión de VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Maraviroc , Persona de Mediana Edad , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/uso terapéutico , Pirrolidinonas/efectos adversos , Pirrolidinonas/uso terapéutico , Raltegravir Potásico , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Insuficiencia del Tratamiento , Carga Viral/efectos de los fármacos , Adulto JovenRESUMEN
The present study describes a follow-up of a prospective and observational cohort of patients infected with HIV-1 and treated with raltegravir for salvage therapy in Brazil. Two groups of patients were analyzed: switching from T20 to RAL (Group 1, n = 9) and salvage therapy containing RAL (Group 2, n = 10). Blood samples were drawn for CD4(+) T-cell counts and HIV-1 viral load determinations. Protease, reverse transcriptase, and integrase genotyping were performed at baseline and at the time of virologic failure. CD4(+) T-cells increased at 6 and 12 months in both groups; HIV-1 viral load was continuously suppressed for Group 1, and for Group 2 it significantly decreased after starting a RAL-containing regimen. Three out of 10 patients from Group 2 could not suppress HIV-1 viral load. The mutations Q148H + G140S were observed for two patients and for the third patient only mutations to PR/RT inhibitors were detected. The genotypic sensitivity score (GSS) was analyzed for all patients of Group 2 and both patients who developed resistance to raltegravir presented a GSS < 2.0 for the RAL-containing scheme, which could be associated to the lack of effectiveness of the proposed scheme. The present study describes, for the first time in Brazil, the close follow-up of a series of patients using a raltegravir-containing HAART, showing the safety of the enfuvirtide switch to RAL and the effectiveness of a therapeutic regimen with RAL in promoting immune reconstitution and suppressing HIV replication, as well as documenting the occurrence of resistance to integrase inhibitors in the country.
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Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Pirrolidinonas/uso terapéutico , Terapia Recuperativa/métodos , Terapia Antirretroviral Altamente Activa , Brasil/epidemiología , Recuento de Linfocito CD4 , Ciclohexanos/uso terapéutico , Enfuvirtida , Estudios de Seguimiento , Técnicas de Genotipaje , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Integrasa de VIH/genética , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/enzimología , VIH-1/fisiología , Humanos , Maraviroc , Mutación , Fragmentos de Péptidos/uso terapéutico , Estudios Prospectivos , ARN Viral/sangre , Raltegravir Potásico , Resultado del Tratamiento , Triazoles/uso terapéutico , Carga Viral , Replicación ViralRESUMEN
The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.
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Carbamatos/efectos adversos , Cardiomiopatías/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Creatina Quinasa/sangre , Ciclohexanos/efectos adversos , Hígado Graso/inducido químicamente , Inhibidores de Fusión de VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de la Proteasa del VIH/efectos adversos , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Organofosfatos/efectos adversos , Pirrolidinonas/efectos adversos , Sulfonamidas/efectos adversos , Triazoles/efectos adversos , Adulto , Carbamatos/uso terapéutico , Ciclohexanos/uso terapéutico , Sustitución de Medicamentos , Quimioterapia Combinada , Hígado Graso/diagnóstico , Furanos , Inhibidores de Fusión de VIH/uso terapéutico , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Cirrosis Hepática/diagnóstico , Masculino , Maraviroc , Organofosfatos/uso terapéutico , Pirrolidinonas/uso terapéutico , Raltegravir Potásico , Sulfonamidas/uso terapéutico , Triazoles/uso terapéuticoRESUMEN
OBJECTIVE: Maraviroc is the first approved drug in a new class of antiretrovirals, the CCR5 antagonists. The objective of this study was to predict the long-term clinical impact and cost-effectiveness of maraviroc in treatment-experienced adults with HIV/AIDS in Mexico. METHODS: The AntiRetroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model was adapted to the Mexican context to predict clinical and economic outcomes of treating with optimized background therapy (OBT) versus testing for viral tropism status and treating with OBT ± maraviroc accordingly in treatment-experienced adults in Mexico. Baseline characteristics and efficacy were from the MOTIVATE trials' screening cohort. Costs and population mortality data were specific to Mexico. Results were reported from the perspective of health care payers in 2008 Mexican pesos (converted to 2008 US$ in parentheses). RESULTS: Compared to treatment with OBT alone, treatment with OBT ± maraviroc contingent on tropism test result increased projected undiscounted life expectancy and discounted quality-adjusted life expectancy from 7.54 to 8.71 years and 4.42 to 4.92 quality-adjusted life years (QALYs), respectively, at an incremental cost of $228,215 (US$21,329). The resultant incremental cost-effectiveness ratio (ICER) was $453,978 (US$42,429) per QALY gained. The ICER was somewhat lower when maraviroc was modeled in individuals susceptible to ≤ 2 components of OBT ($407,329; US$38,069), while the ICER was higher in individuals susceptible to ≥3 OBT components ($718,718; US$67,171). CONCLUSION: In treatment-experienced individuals with HIV/AIDS in Mexico, maraviroc may be cost-effective, particularly in individuals with limited options for active antiretroviral therapy (ART).
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Ciclohexanos/economía , Inhibidores de Fusión de VIH/economía , Infecciones por VIH/economía , Triazoles/economía , Simulación por Computador , Análisis Costo-Beneficio , Ciclohexanos/uso terapéutico , Femenino , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Maraviroc , México , Persona de Mediana Edad , Modelos Biológicos , Años de Vida Ajustados por Calidad de Vida , Triazoles/uso terapéuticoRESUMEN
Entry inhibitor is a new class of drugs that target the viral envelope protein. This region is variable; hence resistance to these drugs may be present before treatment. The aim of this study was to analyze the frequency of patients failing treatment with transcriptase reverse and protease inhibitors that would respond to the entry inhibitors Enfuvirtide, Maraviroc, and BMS-806. The study included 100 HIV-1 positive patients from one outpatient clinic in the city of Sao Paulo, for whom a genotype test was requested due to treatment failure. Proviral DNA was amplified and sequenced for regions of gp120 and gp41. A total of 80 could be sequenced and from those, 73 (91.3%), 5 (6.3%) and 2 (2.5%) were classified as subtype B, F, and recombinants (B/ F and B/C), respectively. CXCR4 co-receptor use was predicted in 30% of the strains. Primary resistance to Enfuvirtide was found in 1.3%, following the AIDS Society consensus list, and 10% would be considered resistant if a broader criterion was used. Resistance to BMS-806 was higher; 6 (7.5%), and was associated to non-B strains. Strikingly, 27.5% of samples harbored one or more mutation among A316T, I323V, and S405A, which have been related to decreased susceptibility of Maraviroc; 15% of them among viruses predictive to be R5. A more common mutation was A316T, which was associated to the Brazilian B strain harboring the GWGR motif at the tip of V3 loop and their derivative sequences. These results may be impact guidelines for genotype testing and treatment in Brazil.
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Ciclohexanos/farmacología , Farmacorresistencia Viral , Inhibidores de Fusión de VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Mutación Missense , Triazoles/farmacología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Adulto , Instituciones de Atención Ambulatoria , Fármacos Anti-VIH/uso terapéutico , Brasil , ADN Viral/química , ADN Viral/genética , Enfuvirtida , Femenino , Proteína gp41 de Envoltorio del VIH/farmacología , Inhibidores de Fusión de VIH/administración & dosificación , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH , Transcriptasa Inversa del VIH , VIH-1/aislamiento & purificación , Humanos , Masculino , Maraviroc , Persona de Mediana Edad , Datos de Secuencia Molecular , Fragmentos de Péptidos/farmacología , Piperazinas/farmacología , Prevalencia , Provirus/genética , Análisis de Secuencia de ADN , Insuficiencia del TratamientoRESUMEN
BACKGROUND: The MERIT study evaluated maraviroc versus efavirenz, both with zidovudine/lamivudine, in treatment-naïve patients with CCR5-tropic (R5) HIV-1. Post hoc analyses previously assessed week 48 outcomes in patients rescreened with R5 virus by a more sensitive tropism assay. METHODS: Week 96 efficacy (post hoc, n = 614) and safety (n = 721) were assessed. RESULTS: Proportions of subjects <50 copies/mL (58.8% maraviroc, 62.7% efavirenz) and time to loss of virologic response (TLOVR) responders (<50 copies/mL: 60.5% vs 60.7%) were similar. Maraviroc recipients had greater CD4 increases (+ 212 vs + 171 cells/mm(3)) and fewer adverse event discontinuations (6.1% vs 15.5%), malignancies, and category C events. CONCLUSION: Week 96 data confirm week 48 observations in MERIT.