ABSTRACT
BACKGROUND: Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an unmet demand for specific and effective therapeutic options. Our objective was to investigate the safety of Maraviroc, a CCR5 antagonist, as a possible mechanism-based add-on therapeutic option for PSD in an open-label proof-of-concept clinical trial. METHODS: We conducted a 10-week clinical trial in which ten patients with subcortical and cortical stroke, suffering from PSD. were administered a daily oral dose of 300 mg Maraviroc. Participants were then monitored for an additional eight weeks. The primary outcome measure was serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. The secondary outcome measure was a change in the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Maraviroc was well tolerated, with no reports of serious adverse events or discontinuations due to intolerance. The MADRS scores substantially reduced from baseline to week 10 (mean change: -16.4 ± 9.3; p < 0.001). By the conclusion of the treatment phase, a favorable response was observed in five patients, with four achieving remission. The time to response was relatively short, approximately three weeks. After the cessation of treatment, MADRS scores increased at week 18 by 6.1 ± 9.6 points (p = 0.014). CONCLUSIONS: Our proof-of-concept study suggests that a daily dosage of 300 mg of Maraviroc may represent a well-tolerated and potentially effective pharmacological approach to treating PSD. Further comprehensive placebo-controlled studies are needed to assess the impact of Maraviroc augmentation on PSD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05932550, Retrospectively registered: 28/06/2023.
Subject(s)
CCR5 Receptor Antagonists , Maraviroc , Proof of Concept Study , Stroke , Humans , Maraviroc/administration & dosage , Maraviroc/therapeutic use , Male , Female , Middle Aged , CCR5 Receptor Antagonists/therapeutic use , CCR5 Receptor Antagonists/administration & dosage , Stroke/complications , Stroke/psychology , Stroke/drug therapy , Aged , Depression/drug therapy , Depression/etiology , Treatment Outcome , Triazoles/therapeutic use , Triazoles/administration & dosage , Adult , Receptors, CCR5/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) is a disabling neurologic disorder resulting from the infection of the CNS by JC polyomavirus in immunocompromised individuals. For the last 2 decades, increasing use of immunotherapies leads to iatrogenic PML. Iatrogenic PML is often associated with signs of inflammation at onset (inflammatory PML) and/or after treatment withdrawal immune reconstitution inflammatory syndrome (PML-IRIS). Although immune reconstitution is a key element for viral clearance, it may also be harmful and induce clinical worsening. A C-C chemokine receptor type 5 (CCR5) antagonist (maraviroc) has been proposed to prevent and/or limit the deleterious immune responses underlying PML-IRIS. However, the data to support its use remain scarce and disputed. METHODS: We conducted a multicenter retrospective cohort study at 8 university hospitals in France and Switzerland by collecting clinical, biological, and radiologic data of patients who developed inflammatory PML (iPML) or PML-IRIS related to immunosuppressive therapies used for chronic inflammatory diseases between 2010 and 2020. We added to this cohort, a meta-analysis of individual case reports of patients with iPML/PML-IRIS treated with maraviroc published up to 2021. RESULTS: Overall, 27 cases were identified in the cohort and 9 from the literature. Among them, 27 met the inclusion criteria: 16 treated with maraviroc and 11 with standard of care (including corticosteroids use). Most cases were related to MS (92.6%) and natalizumab (88%). Inflammatory features (iPML) were present at onset in 12 patients (44.4%), and most patients (92.6%) received corticosteroids within the course of PML. Aggravation due to PML-IRIS was not prevented by maraviroc compared with patients who received only corticosteroids (adjusted odds ratio: 0.408, 95% CI: 0.06-2.63). Similarly, maraviroc did not influence time to clinical worsening due to PML-IRIS (adjusted hazard ratio = 0.529, 95% CI: 0.14-2.0) or disability at the last follow-up (adjusted odds ratio: 2, 95% CI: 0.23-17.3). DISCUSSION: The use of CCR5 blockade did not help to keep deleterious immune reconstitution in check even when associated with corticosteroids. Despite maraviroc's reassuring safety profile, this study does not support its use in iPML/PML-IRIS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence showing that adding maraviroc to the management of iatrogenic iPML/PML-IRIS does not improve the outcome.
Subject(s)
CCR5 Receptor Antagonists/pharmacology , Immune Reconstitution Inflammatory Syndrome/drug therapy , Immune Reconstitution Inflammatory Syndrome/prevention & control , Leukoencephalopathy, Progressive Multifocal/drug therapy , Leukoencephalopathy, Progressive Multifocal/prevention & control , Maraviroc/pharmacology , Adult , CCR5 Receptor Antagonists/administration & dosage , Female , Humans , Immune Reconstitution Inflammatory Syndrome/chemically induced , Leukoencephalopathy, Progressive Multifocal/chemically induced , Male , Maraviroc/administration & dosage , Middle Aged , Outcome Assessment, Health Care , Retrospective Studies , Young AdultABSTRACT
BACKGROUND AND AIMS: Cenicriviroc (CVC) is a C-C chemokine receptors type 2 and 5 dual antagonist under evaluation for treating liver fibrosis in adults with nonalcoholic steatohepatitis (NASH). Year 1 primary analysis of the 2-year CENTAUR study showed that CVC had an antifibrotic effect without impacting steatohepatitis. Herein, we report the final data from year 2 exploratory analyses. APPROACH AND RESULTS: This was a randomized, controlled study of adults with NASH, nonalcoholic fatty liver disease activity score ≥4, and NASH Clinical Research Network stage 1-3 fibrosis. Participants in arms A and C received CVC 150 mg or placebo, respectively, for 2 years; arm B received placebo in year 1 and switched to CVC in year 2. Liver biopsy was performed at baseline, year 1, and year 2. Of 289 randomized participants, 242 entered year 2. At year 2, 24% of patients who switched to CVC and 17% who remained on placebo achieved ≥1-stage fibrosis improvement and no worsening of NASH (P = 0.37). Twice the proportion on CVC who achieved fibrosis response at year 1 maintained benefit at year 2 (60% arm A versus 30% arm C), including 86% on CVC who had stage 3 fibrosis at baseline. Over 2 years, a similar proportion on CVC or placebo achieved ≥1-stage fibrosis improvement and no worsening of NASH (15% arm A versus 17% arm C). In patients with fibrosis responses, we observed consistent reductions in levels of N-terminal type 3 collagen propeptide and enhanced liver fibrosis scores, while increases in aspartate aminotransferase-to-platelet ratio index and Fibrosis-4 scores were consistently observed in nonresponders. Safety profile was comparable across groups. CONCLUSIONS: CVC was well tolerated, and year 2 data corroborate antifibrotic findings from year 1. The majority on CVC who achieved fibrosis response at year 1 maintained it at year 2, with greater effect in advanced fibrosis. ClinicalTrials.gov number, NCT02217475 (CENTAUR).
Subject(s)
Aspartate Aminotransferases/blood , Imidazoles , Liver Cirrhosis , Liver/pathology , Non-alcoholic Fatty Liver Disease , Platelet Count/methods , Sulfoxides , Biopsy/methods , CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/adverse effects , Disease Progression , Drug Monitoring/methods , Female , Humans , Imidazoles/administration & dosage , Imidazoles/adverse effects , Liver Cirrhosis/diagnosis , Liver Cirrhosis/etiology , Liver Cirrhosis/prevention & control , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/drug therapy , Patient Acuity , Receptors, CCR2/metabolism , Sulfoxides/administration & dosage , Sulfoxides/adverse effects , Treatment OutcomeABSTRACT
Clinical management of neuropathic pain is unsatisfactory, mainly due to its resistance to the effects of available analgesics, including opioids. Converging evidence indicates the functional interactions between chemokine and opioid receptors and their influence on nociceptive processes. Recent studies highlight that the CC chemokine receptors type 2 (CCR2) and 5 (CCR5) seem to be of particular interest. Therefore, in this study, we investigated the effects of the dual CCR2/CCR5 antagonist, cenicriviroc, on pain-related behaviors, neuroimmune processes, and the efficacy of opioids in rats after chronic constriction injury (CCI) of the sciatic nerve. To define the mechanisms of action of cenicriviroc, we studied changes in the activation/influx of glial and immune cells and, simultaneously, the expression level of CCR2, CCR5, and important pronociceptive cytokines in the spinal cord and dorsal root ganglia (DRG). We demonstrated that repeated intrathecal injections of cenicriviroc, in a dose-dependent manner, alleviated hypersensitivity to mechanical and thermal stimuli in rats after sciatic nerve injury, as measured by von Frey and cold plate tests. Behavioral effects were associated with the beneficial impact of cenicriviroc on the activation/influx level of C1q/IBA-1-positive cells in the spinal cord and/or DRG and GFAP-positive cells in DRG. In parallel, administration of cenicriviroc decreased the expression of CCR2 in the spinal cord and CCR5 in DRG. Concomitantly, we observed that the level of important pronociceptive factors (e.g., IL-1beta, IL-6, IL-18, and CCL3) were increased in the lumbar spinal cord and/or DRG 7 days following injury, and cenicriviroc was able to prevent these changes. Additionally, repeated administration of this dual CCR2/CCR5 antagonist enhanced the analgesic effects of morphine and buprenorphine in neuropathic rats, which can be associated with the ability of cenicriviroc to prevent nerve injury-induced downregulation of all opioid receptors at the DRG level. Overall, our results suggest that pharmacological modulation based on the simultaneous blockade of CCR2 and CCR5 may serve as an innovative strategy for the treatment of neuropathic pain, as well as in combination with opioids.
Subject(s)
Analgesics/therapeutic use , CCR5 Receptor Antagonists/therapeutic use , Hyperalgesia/drug therapy , Imidazoles/therapeutic use , Neuralgia/drug therapy , Receptors, CCR2/antagonists & inhibitors , Sciatic Neuropathy/complications , Sulfoxides/therapeutic use , Analgesics/administration & dosage , Analgesics/pharmacology , Analgesics, Opioid/pharmacology , Analgesics, Opioid/therapeutic use , Animals , Buprenorphine/pharmacology , Buprenorphine/therapeutic use , CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/pharmacology , Cytokines/biosynthesis , Cytokines/genetics , Dose-Response Relationship, Drug , Drug Synergism , Ganglia, Spinal/metabolism , Gene Expression Regulation/drug effects , Hyperalgesia/etiology , Hyperalgesia/physiopathology , Imidazoles/administration & dosage , Imidazoles/pharmacology , Injections, Spinal , Male , Morphine/pharmacology , Morphine/therapeutic use , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neuralgia/etiology , Neuralgia/physiopathology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Wistar , Receptors, CCR2/biosynthesis , Receptors, CCR2/genetics , Receptors, CCR5/biosynthesis , Receptors, CCR5/genetics , Receptors, Opioid/biosynthesis , Receptors, Opioid/genetics , Spinal Cord/metabolism , Sulfoxides/administration & dosage , Sulfoxides/pharmacologyABSTRACT
Microbicides based on hydrogel have become an effective way to prevent the HIV replication and transmission because of their convenience and prolonging drug release. In this study, a hybrid thermo-sensitive hydrogel constituted by nanosized layered double hydroxides and poloxamer 407 (P407) was constructed and co-loaded with both hydrophobic and hydrophilic drug. The LDH-P407 hydrogel could achieve sol-gel transition at body temperature. The in vivo experiment showed that LDH-P407 hydrogel can achieve controlled release of theaflavin and Nile red (hydrophobic drug model) into blood by vaginal drug delivery, meanwhile the hydrogel showed barely mucosal irritation. In addition, ex vivo experiment showed that the nifeviroc-loaded LDH-P407 hydrogel was able to specifically bind co-receptor CCR5 of DCs cells. Therefore, the LDH-P407 hydrogel would be a promising carrier for intravaginal delivery of anti-HIV drugs.
Subject(s)
Anti-HIV Agents/administration & dosage , Anti-HIV Agents/chemistry , Drug Carriers/chemistry , Hydrogels/chemistry , Hydroxides/chemistry , Temperature , Administration, Intravaginal , Animals , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/chemistry , CCR5 Receptor Antagonists/pharmacology , Drug Carriers/pharmacokinetics , Hydrophobic and Hydrophilic Interactions , Hydroxides/pharmacokinetics , Poloxamer/chemistry , Rabbits , Rheology , Tissue DistributionSubject(s)
Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists/administration & dosage , Cognitive Dysfunction/drug therapy , HIV Infections/complications , Imidazoles/pharmacokinetics , Anti-HIV Agents/cerebrospinal fluid , Anti-HIV Agents/therapeutic use , Cognition/drug effects , Cognitive Dysfunction/cerebrospinal fluid , Cognitive Dysfunction/etiology , HIV Infections/cerebrospinal fluid , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/genetics , HIV-1/isolation & purification , Humans , Imidazoles/cerebrospinal fluid , Imidazoles/therapeutic use , RNA, Viral/cerebrospinal fluid , SulfoxidesABSTRACT
Antiretroviral-releasing vaginal rings are at the forefront of ongoing efforts to develop microbicide-based strategies for prevention of heterosexual transmission of the human immunodeficiency virus (HIV). However, traditional ring designs are generally only useful for vaginal administration of relatively potent, lipophilic, and small molecular weight drug molecules that have sufficient permeability in the non-biodegradable silicone elastomer or thermoplastic polymers. Here, we report a novel, easy-to-manufacture 'exposed-core' vaginal ring that provides sustained release of the protein microbicide candidate 5P12-RANTES, an experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. In vitro release, mechanical, and stability testing demonstrated the utility and practicality of this novel ring design. In a sheep pharmacokinetic model, a ring containing two »-length excipient-modified silicone elastomer cores - each containing lyophilised 5P12-RANTES and exposed to the external environment by two large windows - provided sustained concentrations of 5P12-RANTES in vaginal fluid and vaginal tissue between 10 and 10,000â¯ng/g over 28days, at least 50 and up to 50,000 times the reported in vitro IC50 value.
Subject(s)
CCR5 Receptor Antagonists/administration & dosage , Chemokines, CC/administration & dosage , Contraceptive Devices, Female , Drug Delivery Systems , Administration, Intravaginal , Animals , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists/pharmacokinetics , Chemokines, CC/pharmacokinetics , Delayed-Action Preparations , Female , HIV Infections/prevention & control , Humans , Inhibitory Concentration 50 , SheepABSTRACT
A case of progressive multifocal leukoencephalopathy (PML) is described in an HIV-negative patient with mixed connective-tissue disease (MCTD) on a minimally immunosuppressive treatment with hydroxychloroquine. The patient presented with right-sided weakness, episodes of disorientation and loss of short-term memory and of vision in her right eye. PML was diagnosed by JCV DNA on cerebrospinal fluid and radiological criteria. She was treated with off-label maraviroc and mirtazapine but died two months after hospital admission, despite a surprising decrease in the viral load of cerebrospinal fluid three weeks after starting therapy. Prompt diagnosis and antiviral treatment of PML even in low-risk patients are warranted. Future studies are required to define the therapeutic role of maraviroc (MVC) and mirtazapine in this setting.
Subject(s)
CCR5 Receptor Antagonists/administration & dosage , Leukoencephalopathy, Progressive Multifocal/drug therapy , Maraviroc/administration & dosage , Mirtazapine/administration & dosage , Drug Therapy, Combination , Female , HIV Seronegativity , Humans , Middle AgedABSTRACT
Current approaches do not eliminate all human immunodeficiency virus type 1 (HIV-1) maternal-to-infant transmissions (MTIT); new prevention paradigms might help avert new infections. We administered maraviroc (MVC) to rhesus macaques (RMs) to block CCR5-mediated entry, followed by repeated oral exposure of a CCR5-dependent clone of simian immunodeficiency virus (SIV) mac251 (SIVmac766). MVC significantly blocked the CCR5 coreceptor in peripheral blood mononuclear cells and tissue cells. All control animals and 60% of MVC-treated infant RMs became infected by the 6th challenge, with no significant difference between the number of exposures (P = 0.15). At the time of viral exposures, MVC plasma and tissue (including tonsil) concentrations were within the range seen in humans receiving MVC as a therapeutic. Both treated and control RMs were infected with only a single transmitted/founder variant, consistent with the dose of virus typical of HIV-1 infection. The uninfected RMs expressed the lowest levels of CCR5 on the CD4+ T cells. Ramp-up viremia was significantly delayed (P = 0.05) in the MVC-treated RMs, yet peak and postpeak viral loads were similar in treated and control RMs. In conclusion, in spite of apparent effective CCR5 blockade in infant RMs, MVC had a marginal impact on acquisition and only a minimal impact on the postinfection delay of viremia following oral SIV infection. Newly developed, more effective CCR5 blockers may have a more dramatic impact on oral SIV transmission than MVC.IMPORTANCE We have previously suggested that the very low levels of simian immunodeficiency virus (SIV) maternal-to-infant transmissions (MTIT) in African nonhuman primates that are natural hosts of SIVs are due to a low availability of target cells (CCR5+ CD4+ T cells) in the oral mucosa of the infants, rather than maternal and milk factors. To confirm this new MTIT paradigm, we performed a proof-of-concept study in which we therapeutically blocked CCR5 with maraviroc (MVC) and orally exposed MVC-treated and naive infant rhesus macaques to SIV. MVC had only a marginal effect on oral SIV transmission. However, the observation that the infant RMs that remained uninfected at the completion of the study, after 6 repeated viral challenges, had the lowest CCR5 expression on the CD4+ T cells prior to the MVC treatment appears to confirm our hypothesis, also suggesting that the partial effect of MVC is due to a limited efficacy of the drug. New, more effective CCR5 inhibitors may have a better effect in preventing SIV and HIV transmission.
Subject(s)
CCR5 Receptor Antagonists/administration & dosage , Cyclohexanes/administration & dosage , Infectious Disease Transmission, Vertical/prevention & control , Macaca mulatta , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Acquired Immunodeficiency Syndrome/transmission , Triazoles/administration & dosage , Animals , CCR5 Receptor Antagonists/pharmacokinetics , Cyclohexanes/pharmacokinetics , Humans , Infant , Maraviroc , Palatine Tonsil/chemistry , Serum/chemistry , Treatment Outcome , Triazoles/pharmacokinetics , Viral LoadABSTRACT
PURPOSE OF REVIEW: Although antiretroviral therapy has become more potent and tolerable, adherence remains a barrier to continuous viral suppression and new approaches are needed. PRO 140 is a C-C chemokine receptor 5 (CCR5)-directed mAb with potential for weekly subcutaneous dosing. This review discusses data from the PRO 140 clinical development program including emerging data from ongoing efficacy studies. RECENT FINDINGS: Phase II development of PRO 140 began over a decade ago, and recently initiated phase IIb and III trials are ongoing in study participants with virologic failure and as monotherapy maintenance in virologically suppressed study participants. PRO 140 previously demonstrated potency against CCR5-tropic virus in parenteral formulations with excellent short-term safety and tolerability, and low potential for tropism shifts or resistance. Studies are ongoing in treatment-experienced patients with multidrug resistant virus and as monotherapy maintenance in virologically suppressed patients. Partial data are available from these studies. To date, only a small number of study participants have achieved durable success on monotherapy maintenance. SUMMARY: PRO 140 has demonstrated antiviral potency, a high barrier to resistance, and a promising short-term safety profile. Ongoing trials are exploring efficacy against CCR5-tropic virus resistant to current antiretroviral therapy and safety and efficacy as monotherapy maintenance in individuals with viral suppression.
Subject(s)
Anti-HIV Agents/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , CCR5 Receptor Antagonists/administration & dosage , HIV Antibodies/administration & dosage , HIV Infections/drug therapy , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , HIV Infections/genetics , HIV Infections/metabolism , Humans , Receptors, CCR5/genetics , Receptors, CCR5/metabolismABSTRACT
B07 is a small-molecule CCR5 antagonist-based HIV-1 entry inhibitor that is being developed as an anti-HIV microbicide for preventing sexual transmission of HIV. Here we evaluated its spermicidal and contraceptive potential, including sperm motility, plasma membrane integrity, and contraceptive efficacy tested in rabbits. We found that B07 inhibited sperm motility and movement patterns in a concentration- and time-dependent manner. Within 30â¯min, B07 induced sperm immobilization with the minimum 100% effective concentration and median effective concentration of 640.0 and 64.4⯵g/mL, respectively. The hypo-osmotic swelling test showed that plasma membranes of B07-treated sperms exhibited slight disruption, as verified by electron micrographs. In both B07 gel and N-9 gel groups, not a single implantation site or embryo was observed based on the contraceptive efficacy test in rabbits, indicating that B07 could effectively block the potential of sperm to reach and/or fertilize oocytes. The safety profile of B07 in vivo was evaluated by use of an optimized rabbit vaginal irritation test. While the pathological scores of the N-9 gel group was 14.67⯱â¯1.21, those of the blank control and B07 gel groups were 2.17⯱â¯0.76 and 4.00⯱â¯0.89, respectively, which were within the clinically acceptable range (<8). The proportion of inflammatory cells and CD45+ cells in the cervicovaginal lavages of the B07 gel group showed no significant change compared to those of the control group. Therefore, our results confirmed that B07 exhibited significant spermicidal and contraceptive effects, suggesting its potential for development as a microbicidal spermicide for contraception and prevention of HIV sexual transmission.
Subject(s)
CCR5 Receptor Antagonists/pharmacology , HIV Fusion Inhibitors/pharmacology , HIV Infections/prevention & control , Piperazines/pharmacology , Receptors, CCR5/drug effects , Spermatocidal Agents/pharmacology , Spermatozoa/drug effects , Administration, Intravaginal , Animals , CCR5 Receptor Antagonists/administration & dosage , Dose-Response Relationship, Drug , Female , Gels , HIV Fusion Inhibitors/administration & dosage , HIV Infections/transmission , HIV Infections/virology , Humans , Male , Piperazines/administration & dosage , Pregnancy , Pregnancy Rate , Rabbits , Receptors, CCR5/metabolism , Sperm Motility/drug effects , Sperm-Ovum Interactions/drug effects , Spermatocidal Agents/administration & dosage , Spermatozoa/metabolism , Spermatozoa/ultrastructure , Time FactorsABSTRACT
Blocking lymphocyte trafficking after allogeneic hematopoietic stem cell transplantation is a promising strategy to prevent graft-versus-host disease (GVHD) while preserving the graft-versus-tumor response. Maraviroc, a CCR5 antagonist, has shown promise in clinical trials, presumably by disrupting the migration of effector cells to GVHD target organs. We describe a phosphoflow assay to quantify CCR5 blockade during treatment with maraviroc and used it to evaluate 28 patients in a phase II study. We found that insufficient blockade of CCR5 was associated with significantly worse overall survival (HR, 10.6; 95% CI, 2.2 to 52.0; P = .004) and higher rates of nonrelapse mortality (HR, 146; 95% CI, 1.0 to 20,600; P = .04) and severe acute GVHD (HR, 12; 95% CI, 1.9 to 76.6; P = .009). In addition, we found that pretransplant high surface expression of CCR5 on recipient T cells predicted higher nonrelapse mortality and worse GVHD- and relapse-free survival. Our results demonstrate that pharmacodynamic monitoring of CCR5 blockade unravels interpatient variability in the response to therapy and may serve as a clinically informative biomarker.
Subject(s)
CCR5 Receptor Antagonists , Graft vs Host Disease , Maraviroc , Receptors, CCR5 , Aged , CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/pharmacokinetics , Disease-Free Survival , Female , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Humans , Male , Maraviroc/administration & dosage , Maraviroc/pharmacokinetics , Middle Aged , Survival RateABSTRACT
OBJECTIVES: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. METHODS: MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. RESULTS: Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. CONCLUSIONS: MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.
Subject(s)
Antiretroviral Therapy, Highly Active/methods , CCR5 Receptor Antagonists/administration & dosage , Cyclohexanes/administration & dosage , Drug Substitution , HIV Infections/drug therapy , HIV Protease Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/administration & dosage , Triazoles/administration & dosage , Adult , Antiretroviral Therapy, Highly Active/adverse effects , CCR5 Receptor Antagonists/adverse effects , Cyclohexanes/adverse effects , Drug-Related Side Effects and Adverse Reactions/epidemiology , HIV Protease Inhibitors/adverse effects , HIV-1/isolation & purification , Humans , Maraviroc , RNA, Viral/blood , Reverse Transcriptase Inhibitors/adverse effects , Treatment Outcome , Triazoles/adverse effects , Viral LoadABSTRACT
To assess the efficacy and safety of maraviroc (MVC) administered once-daily in routine clinical practice. A retrospective multicenter study (27 centers in Spain) was conducted. Data were collected from the records of patients starting a regimen with MVC. Laboratory and clinical data were recorded every 3 months the first year and every 6 months thereafter. Data are presented as median and interquartile range. Among 667 patients treated with MVC, 142 (21.3%) received MVC once-daily: 108 (76.1%), 150 mg and 34 (23.9%), and 300 mg. Age was 47 (42-45) years, there were 76.1% men, and 81 (57%) patients had baseline HIV-RNA <50 copies/mL. Viral tropism was R5 in 118 (83.1%) patients. Reasons for prescribing MVC: salvage therapy (36.6%), drug toxicity (31.2%), simplification (16.9%), and immunodiscordant response (7.1%). Median follow-up was 13 (9-16) months. In 95.8%, a PI/r was part of the regimen (67% on dual therapy). At months 12 and 24, 73.3% and 68.2% of patients had HIV-RNA <50 copies/mL, respectively (p = .041 and p < .001 vs. baseline). CD4+ cell count increased by a median of 52 (-36,135) and 84 (-9.5,180) cells/mm3 at 12 and 24 months, respectively (p < .001 and p = .039 vs. baseline). Twenty-five (17.6%) patients discontinued MVC: virologic failure (6), medical decision (5), and other reasons (14). Two patients presented grade 3 adverse events (hypertransaminasemia, hypertriglyceridemia) without the need for MVC withdrawal, whereas MVC was discontinued in two patients due to gastrointestinal toxicity. In routine clinical practice, MVC once-daily combined with at least PI/r was virologically effective and well tolerated in a high percentage of pretreated patients.
Subject(s)
CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/adverse effects , Cyclohexanes/administration & dosage , Cyclohexanes/adverse effects , HIV Infections/drug therapy , Triazoles/administration & dosage , Triazoles/adverse effects , Adult , CD4 Lymphocyte Count , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Longitudinal Studies , Male , Maraviroc , Middle Aged , RNA, Viral/blood , Retrospective Studies , Spain , Treatment Outcome , Viral LoadSubject(s)
CCR5 Receptor Antagonists/administration & dosage , Cyclohexanes/administration & dosage , HIV Infections/drug therapy , Off-Label Use , Triazoles/administration & dosage , Adolescent , CCR5 Receptor Antagonists/adverse effects , Child , Cyclohexanes/adverse effects , Female , Humans , Male , Maraviroc , Retrospective Studies , Treatment Outcome , Triazoles/adverse effectsABSTRACT
We show that intensification of treatment with maraviroc in patients chronically infected with HIV-1 receiving successful long-term antiretroviral therapy was not associated with improvements in HIV-related morbidity, HIV reservoir, microbial translocation, immune activation, or immune exhaustion in either gut or peripheral blood. The measurement of reservoir in both gut and blood longitudinally contributes to a paucity of data in the area.
Subject(s)
Blood/virology , CCR5 Receptor Antagonists/administration & dosage , Cyclohexanes/administration & dosage , Gastrointestinal Tract/virology , HIV Infections/drug therapy , HIV Infections/virology , Triazoles/administration & dosage , Humans , Male , Maraviroc , Middle Aged , Pilot Projects , Prospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis. METHODS: Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat. RESULTS: Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations. CONCLUSIONS: MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis. CLINICAL TRIALS REGISTRATION: NCT01505114.
Subject(s)
CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/adverse effects , Cyclohexanes/administration & dosage , Cyclohexanes/adverse effects , Disease Transmission, Infectious/prevention & control , HIV Infections/prevention & control , Pre-Exposure Prophylaxis/methods , Triazoles/administration & dosage , Triazoles/adverse effects , Adolescent , Adult , Aged , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Double-Blind Method , Homosexuality, Male , Humans , Male , Maraviroc , Middle Aged , Prospective Studies , Young AdultABSTRACT
To investigate the pharmacokinetics/pharmacodynamics of single-dose maraviroc 300 mg in HIV-1 exposure compartments. Maraviroc concentrations in blood, secretions (vaginal, urethral, oral, and rectal), and tissue (vaginal and rectal) were measured, and ex vivo challenge was performed in 54 healthy volunteers to study protection from HIV infection. Maraviroc Cmax occurred within 4 hours in most compartments. Concentrations from 4 to 72 hours were above intracellular (IC) IC90 in all compartments, range 15-8095 ng/mL. Mean AUC0-72 compartment-to-plasma ratios were highest in the rectum (45-819) and urethra (144) compared with the female genital tract (1.6-4.8) and saliva (0.2). No sex differences in AUC0-72 or Cmax were observed. No ex vivo protection from HIV-1BaL occurred in rectal or vaginal tissue. Despite high and sustained concentrations, single-dose maraviroc was not protective against ex vivo challenge of vaginal/rectal tissue.
Subject(s)
CCR5 Receptor Antagonists/pharmacokinetics , Cyclohexanes/pharmacokinetics , HIV Fusion Inhibitors/pharmacokinetics , HIV Infections/prevention & control , HIV Infections/virology , Pre-Exposure Prophylaxis , Triazoles/pharmacokinetics , Administration, Oral , Adult , CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/pharmacology , Cyclohexanes/administration & dosage , Cyclohexanes/pharmacology , Female , HIV Fusion Inhibitors/administration & dosage , HIV Fusion Inhibitors/pharmacology , HIV-1/drug effects , Healthy Volunteers , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/virology , Male , Maraviroc , Models, Biological , Randomized Controlled Trials as Topic , Rectum/drug effects , Rectum/virology , Saliva/drug effects , Saliva/virology , Treatment Outcome , Triazoles/administration & dosage , Triazoles/pharmacology , Urethra/drug effects , Urethra/virology , Vagina/drug effects , Vagina/virologyABSTRACT
BACKGROUND & AIMS: Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC's anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis. METHODS: Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses. RESULTS: CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney weight. CONCLUSIONS: CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC's antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475).
Subject(s)
CCR5 Receptor Antagonists/therapeutic use , Imidazoles/therapeutic use , Kidney Diseases/drug therapy , Non-alcoholic Fatty Liver Disease/drug therapy , Animals , CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/pharmacology , Chemotaxis , Fibrosis , Imidazoles/administration & dosage , Imidazoles/pharmacology , Kidney Diseases/pathology , Macrophages/drug effects , Male , Mice , Mice, Inbred C57BL , Monocytes/drug effects , Non-alcoholic Fatty Liver Disease/pathology , Rats , Rats, Sprague-Dawley , Receptors, CCR2/antagonists & inhibitors , SulfoxidesABSTRACT
To date there are no approved antiviral drugs for the treatment of Ebola virus disease (EVD). While a number of candidate drugs have shown limited efficacy in vitro and/or in non-human primate studies, differences in experimental methodologies make it difficult to compare their therapeutic effectiveness. Using an in vitro model of Ebola Zaire replication with transcription-competent virus like particles (trVLPs), requiring only level 2 biosafety containment, we compared the activities of the type I interferons (IFNs) IFN-α and IFN-ß, a panel of viral polymerase inhibitors (lamivudine (3TC), zidovudine (AZT) tenofovir (TFV), favipiravir (FPV), the active metabolite of brincidofovir, cidofovir (CDF)), and the estrogen receptor modulator, toremifene (TOR), in inhibiting viral replication in dose-response and time course studies. We also tested 28 two- and 56 three-drug combinations against Ebola replication. IFN-α and IFN-ß inhibited viral replication 24 hours post-infection (IC50 0.038µM and 0.016µM, respectively). 3TC, AZT and TFV inhibited Ebola replication when used alone (50-62%) or in combination (87%). They exhibited lower IC50 (0.98-6.2µM) compared with FPV (36.8µM), when administered 24 hours post-infection. Unexpectedly, CDF had a narrow therapeutic window (6.25-25µM). When dosed >50µM, CDF treatment enhanced viral infection. IFN-ß exhibited strong synergy with 3TC (97.3% inhibition) or in triple combination with 3TC and AZT (95.8% inhibition). This study demonstrates that IFNs and viral polymerase inhibitors may have utility in EVD. We identified several 2 and 3 drug combinations with strong anti-Ebola activity, confirmed in studies using fully infectious ZEBOV, providing a rationale for testing combination therapies in animal models of lethal Ebola challenge. These studies open up new possibilities for novel therapeutic options, in particular combination therapies, which could prevent and treat Ebola infection and potentially reduce drug resistance.