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Le Infezioni in Medicina Mar 2015In our HIV outpatient centre where over 1,200 patients are followed, maraviroc as an entry inhibitor was introduced in 2010. We aimed to assess the background, the...
In our HIV outpatient centre where over 1,200 patients are followed, maraviroc as an entry inhibitor was introduced in 2010. We aimed to assess the background, the therapeutic challenges and the prospective monitoring of all patients treated with a combination antiretroviral therapy (cART) including maraviroc. Sixty-six patients started a maraviroc-containing cART with a history of HIV infection lasting 13.9±10.7 years. This interim analysis presents patients who had at least 12 (mean 16.9±12.8) months of follow-up. One to 17 previous cART changes prompted the introduction of maraviroc in rescue regimens in the great majority of patients considered (53 of 66); in 13 cases, maraviroc was given to patients with advanced HIV disease and no immune recovery after 2-3 years of a virologically-effective cART. The most frequent companion antiretroviral agents were: darunavir/ritonavir (51 cases), raltegravir (49 subjects), and etravirine (36 cases). The most common underlying conditions were: AIDS (41 cases), liver cirrhosis (21), AIDS-related or other malignancies (20 cases), major cardiovascular events (18 cases), osteonecrosis and haemodialysis-treated kidney failure (3 cases each). A chronic HCV and HBV hepatitis were of concern in 25 and 13 patients. The addition of maraviroc added favourably to clinical-laboratory markers of HIV disease progression, and those of comorbid conditions. HIV viraemia became (or remained) undetectable in 55 patients of 66 (83.3%). An improvement in CD4+ count was observed in all 66 patients, based on a mean 24.9±19.2% increase versus baseline, paralleled by an improvement in mean absolute CD4+ count of 134.7±121.1 cells/μL. A tendency towards an increased mean and peak CD4+ count was observed in the subgroup receiving a maraviroc-raltegravir-based cART. As no clinical-laboratory adverse events attributable to maraviroc occurred, nobody discontinued the study drug. Only mild-transient gastrointestinal disturbances, fatigue and anorexia, were reported during maraviroc administration, but their relationship with the study drug was difficult to assess because of the multiple comorbidities and polypharmacy. Our preliminary experience with maraviroc, even considering the limits of the proportionally reduced sample, the patients' salvage stage of advanced disease and the related-unrelated morbidities, underlines its excellent efficacy and safety profile.
Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Comorbidity; Cyclohexanes; Female; Follow-Up Studies; HIV Infections; Humans; Male; Maraviroc; Middle Aged; Prospective Studies; Treatment Outcome; Triazoles; Viral Load
PubMed: 25819049
DOI: No ID Found -
AIDS and Behavior Dec 2022HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current...
Sexual behavior and medication adherence in men who have sex with men participating in a pre-exposure prophylaxis study of combinations of Maraviroc, Tenofovir Disoproxil Fumarate and/or Emtricitabine (HPTN 069/ACTG 5305).
HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current analyses assessed antiretroviral (ARV) plasma concentrations in relation to sexual behavior in 224 cisgender men who have sex with men and 2 transgender women at risk for HIV. Poisson generalized estimating equations (GEE) regression were used to test for associations between self-reported sexual behavior, sociodemographic, behavioral variables, and study drug levels The median (IQR) age was 30 [25, 37] years old; 48.2% had completed college; 27.4% were Black and 21.7% Latino. At weeks 24 and 48, one third of participants reported condomless anal sex (CAS) in the prior month with more than one partner. CAS was associated with daily ARV drug use (χ = 12.64, p = 0.002). Older individuals and those with greater education were more likely to ingest ARV drugs daily (χ = 9.36, p = 0.009 and χ = 8.63, p = 0.013, respectively), while neither race nor ethnicity was associated with daily ARV drug use. Participants who reported recent condomless anal sex and/or advanced education had higher rates of daily ARV drug use. These data support the need for ongoing adherence counseling in clinical trials of new PrEP modalities.
Topics: Male; Female; Humans; Pre-Exposure Prophylaxis; Emtricitabine; Tenofovir; Maraviroc; Homosexuality, Male; Anti-HIV Agents; HIV Infections; Sexual and Gender Minorities; Medication Adherence; Sexual Behavior; Anti-Retroviral Agents
PubMed: 35687192
DOI: 10.1007/s10461-022-03736-z -
Biochemical and Biophysical Research... Dec 2020Antiretroviral therapy has slowed the HIV/AIDS pandemic and is currently being used as a prophylactic measure for individuals at high risk of infection. However,...
Antiretroviral therapy has slowed the HIV/AIDS pandemic and is currently being used as a prophylactic measure for individuals at high risk of infection. However, concerns over adverse effects of long-term use need to be explored. We hypothesize that this may occur, at least in part, through off-target effects via select steroid receptors (SRs) that broadly regulate multiple physiological processes. We investigated the effects of maraviroc (MVC), tenofovir disoproxil fumarate (TDF), and dapivirine (DPV) on progesterone receptor B (PR-B) transcriptional activity. We found that MVC and TDF activate PR-B transcription in the absence of progestogens on a PR-regulated promoter reporter construct and on endogenous PR-regulated genes. MVC and TDF exhibited no direct binding to PR-B; however, increased PR-B phosphorylation was detected with TDF but not MVC. DPV transactivated gilz and ptgs2 in the absence of progestogens and exhibited PR-B binding while showing no effects on phosphorylation, suggesting that it may activate PR-B through a direct mechanism. Our study shows that potential off-target immunomodulatory effects of MVC, TDF and DPV occur in vitro and these are most likely mediated by different mechanisms of PR-B activation.
Topics: Anti-HIV Agents; Binding, Competitive; Cell Line; Contraceptive Agents, Hormonal; HIV Infections; HIV-1; Humans; Immunologic Factors; In Vitro Techniques; Levonorgestrel; Maraviroc; Phosphorylation; Progesterone Congeners; Pyrimidines; Receptors, Progesterone; Tenofovir; Transcriptional Activation
PubMed: 33012509
DOI: 10.1016/j.bbrc.2020.09.107 -
Blood Feb 2017Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Lymphocyte trafficking...
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Lymphocyte trafficking via chemokine receptors such as CCR5 plays a critical role in alloreactive responses, and previous data suggest that CCR5 blockade with maraviroc results in a low incidence of visceral GVHD. However, the full scope of clinical and immunologic effects of CCR5 blockade in HSCT has not been described. We compared a cohort of patients enrolled on a trial of reduced-intensity allo-HSCT with standard GVHD prophylaxis plus maraviroc to a contemporary control cohort receiving standard GVHD prophylaxis alone. Maraviroc treatment was associated with a lower incidence of acute GVHD without increased risk of disease relapse, as well as reduced levels of gut-specific markers. At day 30, maraviroc treatment increased CCR5 expression on T cells and dampened T-cell activation in peripheral blood without impairing early immune reconstitution or increasing risk for infections. Patients who developed acute GVHD despite maraviroc prophylaxis showed increased T-cell activation, naive T-cell skewing, and elevated serum CXCL9 and CXCL10 levels. Collectively, these data suggest that maraviroc effectively protects against GVHD by modulating alloreactive donor T-cell responses, and that CXCR3 signaling may be an important resistance mechanism to CCR5 blockade in GVHD.
Topics: Adult; Aged; Antigens, Neoplasm; Biomarkers, Tumor; CCR5 Receptor Antagonists; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunity, Cellular; Interleukin-15; Lectins, C-Type; Lymphocyte Activation; Male; Middle Aged; Pancreatitis-Associated Proteins; Receptors, CCR5; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome; Young Adult
PubMed: 28057639
DOI: 10.1182/blood-2016-08-735076 -
Current Opinion in HIV and AIDS Mar 2009Small molecule inhibitors targeting the CCR5 coreceptor represent a new class of drugs for treating HIV-1 infection. Maraviroc has received regulatory approvals, and... (Review)
Review
PURPOSE OF REVIEW
Small molecule inhibitors targeting the CCR5 coreceptor represent a new class of drugs for treating HIV-1 infection. Maraviroc has received regulatory approvals, and vicriviroc is in phase 3 trials. Understanding how resistance to these drugs develops and is diagnosed is essential to guide clinical practice. We review what has been learned from in-vitro resistance studies, and how this relates to what is being seen, or can be anticipated, in clinical studies.
RECENT FINDINGS
The principal resistance pathway in vitro involves continued use of CCR5 in an inhibitor-insensitive manner; the resistant viruses recognize the inhibitor-CCR5 complex, as well as free CCR5. Switching to use the CXCR4 coreceptor is rare. The principal genetic pathway involves accumulating 2-4 sequence changes in the gp120 V3 region, but a non-V3 pathway is also known. The limited information available from clinical studies suggests that a similar escape process is followed in vivo. However, the most common change associated with virologic failure involves expansion of pre-existing, CXCR4-using viruses that are insensitive to CCR5 inhibitors.
SUMMARY
HIV-1 escapes small molecule CCR5 inhibitors by continuing to use CCR5 in an inhibitor-insensitive manner, or evades them by expanding naturally insensitive, CXCR4-using variants.
Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; Drug Resistance, Viral; HIV Envelope Protein gp120; HIV Fusion Inhibitors; HIV-1; Humans; Maraviroc; Mutation, Missense; Piperazines; Pyrimidines; Triazoles
PubMed: 19339950
DOI: 10.1097/COH.0b013e3283223d46 -
International Journal of Molecular... Dec 2022Cysteine-cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5...
Cysteine-cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists have been investigated in clinical trials, only Maraviroc has been licensed for use in the treatment of HIV patients. This indicates that there is a need for novel CCR5 antagonists. Keeping this in mind, the present study was designed. The active CCR5 inhibitors with known IC value were selected from the literature and utilized to develop a ligand-based common feature pharmacophore model. The validated pharmacophore model was further used for virtual screening of drug-like databases obtained from the Asinex, Specs, InterBioScreen, and Eximed chemical libraries. Utilizing computational methods such as molecular docking studies, molecular dynamics simulations, and binding free energy calculation, the binding mechanism of selected inhibitors was established. The identified Hits not only showed better binding energy when compared to Maraviroc, but also formed stable interactions with the key residues and showed stable behavior throughout the 100 ns MD simulation. Our findings suggest that Hit1 and Hit2 may be potential candidates for CCR5 inhibition, and, therefore, can be considered for further CCR5 inhibition programs.
Topics: Humans; Maraviroc; HIV; Molecular Docking Simulation; Cysteine; HIV Infections; Pharmacophore; Receptors, Chemokine; Molecular Dynamics Simulation; Receptors, CCR5; HIV Fusion Inhibitors
PubMed: 36555761
DOI: 10.3390/ijms232416122 -
Journal of Pharmaceutical and... Sep 2014Topical microbicidal agents are being actively pursued as a modality to prevent HIV viral transmission during sexual intercourse. Quantification of antiretroviral agents...
Dual quantification of dapivirine and maraviroc in cervicovaginal secretions from ophthalmic tear strips and polyester-based swabs via liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis.
BACKGROUND
Topical microbicidal agents are being actively pursued as a modality to prevent HIV viral transmission during sexual intercourse. Quantification of antiretroviral agents in specimen sources where antiviral activity is elicited is critical, and drug measurements in cervicovaginal fluid can provide key information on local drug concentrations. Two antiretroviral drugs, dapivirine and maraviroc, have gained interest as vaginal microbicidal agents, and rugged methods are required for their quantification in cervicovaginal secretions.
METHODS
Cervicovaginal fluid spiked with dapivirine and maraviroc were applied to ophthalmic tear strips or polyester-based swabs to mimic collection procedures used in clinical studies. Following sample extraction and the addition of isotopically labeled internal standards, samples were subjected to liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis using a Waters BEH C8, 50mm×2.1mm, 1.7μm particle size column, on an API 4000 mass analyzer operated in selective reaction monitoring mode. The method was validated according to FDA Bioanalytical Method Validation guidelines.
RESULTS
Due to the disparate saturation capacity of the tested collection devices, the analytical measuring ranges for dapivirine and maravirocin cervicovaginal fluid on the ophthalmic tear strip were 0.05-25ng/tear strip, and 0.025-25ng/tear strip, respectively. As for the polyester-based swab, the analytical measuring ranges were 0.25-125ng/swab for dapivirine and 0.125-125ng/swab for maraviroc. Dilutional studies were performed for both analytes to extended ranges of 25,000ng/tear strip and 11,250ng/swab. Standard curves were generated via weighted (1/x(2)) linear or quadratic regression of calibrators. Precision, accuracy, stability and matrix effects studies were all performed and deemed acceptable according to the recommendations of the FDA Bioanalytical Method Validation guidelines.
CONCLUSIONS
A rugged LC-MS/MS method for the dual quantification of dapivirine and maraviroc in cervicovaginal fluid using two unique collection devices has been developed and validated. The described method meets the criteria to support large research trials.
Topics: Antiviral Agents; Calibration; Cervix Uteri; Chromatography, Liquid; Cyclohexanes; Female; Humans; Maraviroc; Polyesters; Pyrimidines; Reagent Strips; Tandem Mass Spectrometry; Triazoles; Vagina
PubMed: 25005891
DOI: 10.1016/j.jpba.2014.06.018 -
Antimicrobial Agents and Chemotherapy Dec 2013This open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy...
This open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (Cmax), the concentration at end of dosing interval (Cτ), and the area under the curve over dosing interval (AUCτ). Safety and tolerability were also assessed. MVC geometric mean AUCτ, Cmax, and Cτ were increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUCτ, Cmax, and Cτ decreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected.
Topics: Adult; Anti-HIV Agents; Area Under Curve; Carbamates; Cyclohexanes; Drug Administration Schedule; Drug Combinations; Drug Dosage Calculations; Drug Interactions; Furans; Humans; Male; Maraviroc; Middle Aged; Organophosphates; Ritonavir; Sulfonamides; Triazoles
PubMed: 24080663
DOI: 10.1128/AAC.01098-13 -
British Journal of Clinical Pharmacology Apr 2008Two studies were conducted to: (i) quantify the amount of drug-related radioactivity in blood, plasma, urine and faeces following a (14)C-labelled dose of maraviroc; and... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Two studies were conducted to: (i) quantify the amount of drug-related radioactivity in blood, plasma, urine and faeces following a (14)C-labelled dose of maraviroc; and (ii) investigate the pharmacokinetics, safety and tolerability of intravenous (i.v.) maraviroc and determine the absolute bioavailability of oral maraviroc. Metabolite profiling was also conducted. Data from both of these studies were used to construct a mass-balance model for maraviroc.
METHODS
Study 1 was an open-label study in three healthy male subjects. All subjects received a single 300-mg oral solution dose of (14)C-labelled maraviroc. Study 2 included two cohorts of subjects. Cohort 1 involved a double-blind (third party open), four-way crossover study where eight subjects received escalating i.v. doses of maraviroc (3, 10 and 30 mg) with placebo insertion. Cohort 2 involved an open, two-way crossover study where 12 subjects received 30 mg maraviroc by i.v. infusion and 100 mg maraviroc orally in random order. In study 1, blood samples and all urine and faeces were collected up to at least 120 h postdose. In study 2, blood samples were taken at intervals up to 48 h postdose. Urine was also collected up to 24 h postdose in cohort 1 only.
RESULTS
After oral administration in study 1, maraviroc was rapidly absorbed with a plasma T(max) reached by 2 h postdose for all three subjects. The maximum concentrations of radioactivity also occurred within 2 h for all subjects. There was a higher amount of radioactivity in plasma than in blood (blood/plasma ratio approximately 0.6 for AUC(t) and C(max)). Unchanged maraviroc was the major circulating component in plasma, accounting for approximately 42% of the circulating radioactivity. Following a 300-mg (14)C-labelled maraviroc dose, means of 76.4% and 19.6% of radioactivity were recovered in the faeces and urine, respectively. The mean total recovery of dosed radioactivity was 96%, with the majority of radioactivity being recovered within 96 h postdose. Profiling of the urine and faeces showed similar and extensive metabolism in all subjects. Unchanged maraviroc was the major excreted component (33%). The major metabolic pathways were determined and involved oxidation and N-dealkylation. Intravenous doses of maraviroc (3-30 mg) were well tolerated in study 2, and drug exposure was approximately proportional to dose within the studied range. Approximately 23% of total clearance (44 l h(-1)) was accounted for by renal clearance (10.2 l h(-1)). Mean volume of distribution at steady state was 194 l. Absolute bioavailability of a 100-mg oral tablet dose, by comparison with a 30-mg i.v. dose, was calculated to be 23.1%.
CONCLUSIONS
Maraviroc is rapidly absorbed and extensively metabolized, although unchanged maraviroc is the major circulating component in plasma and is the major excreted component after oral dosing. The pharmacokinetics of maraviroc after i.v. administration is approximately proportional over the dose range studied. Renal clearance contributes 23% of total clearance. The absolute bioavailability of 100 mg oral maraviroc is 23%.
Topics: Administration, Oral; Adolescent; Adult; Aged; Biological Availability; CCR5 Receptor Antagonists; Cyclohexanes; Double-Blind Method; Humans; Male; Maraviroc; Middle Aged; Triazoles
PubMed: 18333867
DOI: 10.1111/j.1365-2125.2008.03137.x -
Virology Dec 2017HIV subtypes not only predominate in different geographical regions but also differ in key phenotypic characteristics. To determine if genotypic and/or phenotypic...
HIV subtypes not only predominate in different geographical regions but also differ in key phenotypic characteristics. To determine if genotypic and/or phenotypic differences in the Envelope (Env) glycoprotein can explain subtype related differences, we cloned 37 full length Envs from Subtype B and AE HIV infected individuals from Singapore. Our data demonstrates that CRF01_AE Envs have lower Potential N Glycosylation Sites and higher risk of ×4 development. Phenotypically, CRF01_AE were less infectious than subtype B Envs in cells expressing low levels of CCR5. Moreover, the Maraviroc IC was higher for subtype B Envs and correlated with infectivity in low CCR5 expressing cells as well as PNGS. Specifically, the glycosylation site N301 in the V3 loop was seen less frequently in AE subtype and CXCR4 topic viruses. CRF01_AE differs from B subtype in terms of CCR5 usage and Maraviroc susceptibility which may have implications for HIV pathogenesis and virus evolution.
Topics: Cell Line; Cloning, Molecular; Cyclohexanes; Gene Expression Regulation, Viral; Glycosylation; HIV-1; Humans; Maraviroc; Models, Molecular; Protein Conformation; Receptors, CCR5; Triazoles; Virus Replication; env Gene Products, Human Immunodeficiency Virus
PubMed: 29020646
DOI: 10.1016/j.virol.2017.09.026