cenicriviroc and HIV-Infections

The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite the success of antiretroviral drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the deadliest diseases with a mortality of one million lives in 2016. Thus, there emerges an urgency of developing a novel anti-retroviral agent that combat resistant HIV strains. The clinical development of ART from a single drug regimen to current triple drug combination is very slow. The progression in the structural biology of the viral envelope prompted the discovery of novel targets, which can be demonstrated a proficient approach for drug design of anti-retroviral agents. The current review enlightens the recent updates in the structural biology of the viral envelope and focuses on CCR5 as a validated target as well as ways to overcome CCR5 resistance. The article also throws light on the SAR studies and most prevalent mutations in the receptor for designing CCR5 antagonists that can combat HIV-1 infection. To conclude, the paper lists diversified scaffolds that are in pipeline by various pharmaceutical companies that could provide an aid for developing novel CCR5 antagonists.

Topics: Anti-Retroviral Agents; CCR5 Receptor Antagonists; Drug Design; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Receptors, CCR5

The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists. Areas covered: This review aims to survey the current status of 'next generation' CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies. Expert opinion: The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.

Topics: Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; Drug Design; HIV Infections; Humans; Imidazoles; Maraviroc; Sulfoxides; Triazoles

The C-C chemokine receptor Type 5 (CCR5) is a key receptor for human immunodeficiency virus type 1 (HIV-1) entry into T-cells and a variant allele, CCR5 delta-32, is associated with decreased viral replication and disease progression. Active HIV-1 replication is highly associated with accelerated rates of hepatic fibrosis. We postulated that CCR5 plays a role in the development of hepatic fibrosis and evaluated the longitudinal effect of natural or drug-induced CCR5 mutation and blockade on biomarkers of liver fibrosis in HIV-1 patients.. To accomplish this goal, we examined 2 distinct cohorts. First, we evaluated fibrosis markers in the Multicenter Hemophilia Cohort Studies (MHCS), which included subjects with HIV and hepatitis C virus (HCV) coinfection with the CCR5 delta-32 allele. We also evaluated an HIV-1 infected cohort that was treated with a dual CCR5/CCR2 antagonist, cenicriviroc. The enhanced liver fibrosis (ELF) index was validated against liver histology obtained from HCV/HIV and HCV patients and demonstrated strong correlation with fibrosis stage.. In both the MHCS patients and patients treated with cenicriviroc, CCR5 mutation or blockade was associated with a significant decrease in the ELF index. Among the patients with the delta-32 allele, the ELF index rate significantly decreased in sequential samples as compared to CCR5 wild-type patients (P = .043). This was not observed in control subjects treated with efavirenz nor with a lower dose of 100 mg cenicriviroc.. These findings suggest that hepatic fibrosis in HIV-1 infected patients can be modulated by the mutation of CCR5 and/or use of CCR5/CCR2 blockade agents.. NCT01338883.

Topics: Adolescent; Adult; Aged; Alleles; Biomarkers; CCR5 Receptor Antagonists; Child; Child, Preschool; Cohort Studies; Coinfection; Double-Blind Method; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Mutation; Observational Studies as Topic; Receptors, CCR5; Sulfoxides; Young Adult

To compare the efficacy, safety, and anti-inflammatory effects of cenicriviroc (CVC), an oral, once-daily C-C chemokine receptor types 5 and 2 antagonist, with those of efavirenz (EFV) in treatment-naive, HIV-1-infected adults.. A 48-week, randomized, double-blind, double-dummy phase 2b trial at 43 institutions (USA and Puerto Rico).. Study participants (HIV-1 RNA ≥1000 copies/ml, CD4 cell count ≥200 cells/μl, C-C chemokine receptor type 5-tropic virus) were randomized 2 : 2 : 1 to CVC 100 mg (CVC100), CVC 200 mg (CVC200), or EFV 600 mg, each administered with emtricitabine/tenofovir disoproxil fumarate. Key end points were virologic success (HIV-1 RNA <50 copies/ml) at week 24 (primary) and week 48 (secondary), safety/tolerability at weeks 24 and 48. Study sites and patients remained blinded until week 48.. A total of 143 patients were randomized (CVC100, n = 59; CVC200, n = 56; EFV, n = 28). Virologic success was obtained at week 24 in 76, 73, and 71% of study participants for CVC100, CVC200, and EFV, respectively (all P > 0.05 versus EFV), and at week 48 in 68, 64, and 50%, respectively (all P > 0.05 versus EFV). Resistance mutations emerged in five and zero CVC and EFV-treated study participants, respectively. Virologic nonresponse and nucleoside reverse transcriptase inhibitor resistance decreased when CVC minimum plasma concentration was at least 47.8 ng/ml. Treatment-related adverse events of at least grade 2 and discontinuations because of adverse events were less frequent in CVC-treated study participants. Total and low-density lipoprotein cholesterol decreased with CVC, but increased with EFV. C-C chemokine ligand type 2 (CCL2) (aka monocyte chemotactic protein-1) increased in a dose-dependent manner, whereas soluble CD14 levels decreased with CVC.. CVC showed efficacy and favorable safety in treatment-naive HIV-1-infected study participants, supporting selection of CVC200 for phase 3 studies.. NCT01338883.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Double-Blind Method; Female; Genotype; HIV Infections; HIV-1; Humans; Imidazoles; Immunologic Factors; Male; Middle Aged; Puerto Rico; Receptors, CXCR5; Receptors, HIV; Sulfoxides; Treatment Outcome; United States; Viral Load; Viral Tropism; Young Adult

To determine the antiviral activity, pharmacokinetics, pharmacodynamics, safety, and tolerability of several dose levels of oral TBR-652 monotherapy in HIV-1-infected, antiretroviral experienced, CCR5 antagonist-naive subjects.. Double-blind placebo-controlled study in the United States and Argentina.. Subjects were randomized in a ratio of 4:1 per dose level to TBR-652 (25, 50, 75, 100, or 150 mg) or placebo, taken once daily for 10 days. Changes from baseline in HIV-1 RNA and CD4 cell counts were measured through day 40 and for monocyte chemotactic protein-1 (MCP-1), high-sensitivity C-reactive protein (hs-CRP), and IL-6 at day 10. Pharmacokinetic data were analyzed using noncompartmental statistics. Laboratory and clinical adverse events (AEs) and electrocardiogram changes were recorded.. Maximum median reductions in HIV-1 RNA values for the 25, 50, 75, and 150 mg doses were -0.7, -1.6, -1.8, and -1.7 log10 copies per milliliter, respectively. All changes were significant. Median time to nadir was 10-11 days. Suppression persisted well into the posttreatment period. Mean MCP-1 increased significantly by day 10 in the 50-mg and 150-mg dose groups. Effects on CD4 cell counts, hs-CRP, and IL-6 levels were negligible. TBR-652 was generally safe and well tolerated, with no withdrawals due to AEs.. TBR-652 caused significant reductions in HIV-1 RNA at all doses. Significant increases in MCP-1 levels suggested a strong CCR2 blockade. TBR-652 was generally well tolerated with no dose-limiting AEs. Pharmacodynamics indicate that TBR-652 warrants further investigation as an unboosted once-daily oral CCR5 antagonist with potentially important CCR2-mediated anti-inflammatory effects.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Biomarkers; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Double-Blind Method; Female; Half-Life; HIV Infections; HIV-1; Humans; Imidazoles; Inflammation; Male; Middle Aged; Receptors, CCR2; RNA, Viral; Sulfoxides; Young Adult

Topics: Chromatography, Liquid; Drug Stability; HIV Infections; Humans; Imidazoles; Limit of Detection; Reproducibility of Results; Sulfoxides; Tandem Mass Spectrometry

In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies.

Topics: Anti-Retroviral Agents; Chalcones; Chenodeoxycholic Acid; Cholic Acids; Clinical Trials, Phase III as Topic; Drug Interactions; HIV Infections; Humans; Imidazoles; Non-alcoholic Fatty Liver Disease; Propionates; Pyridazines; Sulfoxides; Uracil

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cognition; Cognitive Dysfunction; HIV Infections; HIV-1; Humans; Imidazoles; RNA, Viral; Sulfoxides

Incidences of cardiovascular diseases (CVD) are high among virologically suppressed HIV-infected individuals. Monocyte activation and trafficking are key mechanisms in the evolution of CVD. We studied the ability of cenicriviroc (CVC), a dual C-C chemokine receptor type 2 (CCR2) and CCR5 antagonist, to influence the migration of monocytes from HIV-infected individuals on antiretroviral therapy (ART). Monocytes were derived from 23 ART-suppressed HIV-infected and 16 HIV-uninfected donors. In a trans-endothelial migration model, monocytes, and human aortic endothelial cells (HAoECs) were exposed to cenicriviroc and migrated monocytes, quantified. Expression of CCR2 and CCR5 on monocytes and adhesion molecules (E-selectin, ICAM-1, VCAM-1, PECAM-1, and CD99) on HAoECs were measured. The single antagonists, BMS-22 (CCR2), and maraviroc (CCR5), served as controls. When both HAoECs and monocytes together were exposed to the antagonists, cenicriviroc led to a greater decrease in monocyte migration compared to BMS-22 or vehicle in both HIV-infected and HIV-uninfected groups (P < 0.05), with maraviroc having no inhibitory effect. Cenicriviroc treatment of HAoECs alone decreased monocyte migration in the HIV-infected group when compared to vehicle (P < 0.01). Inhibition of migration was not evident when monocytes alone were exposed to cenicriviroc, BMS-22 or maraviroc. Incubation of HAoECs with cenicriviroc decreased E-selectin expression (P = 0.045) but had limited effects on the other adhesion molecules. Cenicriviroc inhibits monocyte trans-endothelial migration more effectively than single chemokine receptor blockade, which may be mediated via disruption of monocyte-endothelial tethering through reduced E-selectin expression. Cenicriviroc should be considered as a therapeutic intervention to reduce detrimental monocyte trafficking.

Topics: 12E7 Antigen; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Aorta; Atherosclerosis; CCR5 Receptor Antagonists; Cell Adhesion Molecules; Cells, Cultured; Drug Evaluation, Preclinical; E-Selectin; Endothelial Cells; Female; HIV Infections; Humans; Imidazoles; Male; Maraviroc; Middle Aged; Monocytes; Receptors, CCR2; Receptors, CCR5; Sulfoxides; Transendothelial and Transepithelial Migration

Cenicriviroc is a potent antagonist of the chemokine coreceptors 5 and 2 (CCR5/CCR2) and blocks HIV-1 entry. The CCR5 inhibitor maraviroc has been shown in tissue culture to be able to repel cell-free virions from the cell surface into extracellular space. We hypothesized that cenicriviroc might exhibit a similar effect, and tested this using clinical samples from the Phase IIb study 652-2-202, by measuring rates of intracellular DNA decline. We also monitored viral RNA levels in culture fluids.. We infected PM-1 cells with CCR5-tropic HIV-1 BaL in the presence or absence of inhibitory concentrations of cenicriviroc (20 nM) or maraviroc (50 nM) or controls. Viral load levels and p24 were measured by ELISA, quantitative PCR and quantitative real-time reverse transcription PCR at 4 h post-infection. Frozen PBMC DNA samples from 30 patients with virological success in the Phase IIb study were studied, as were early and late reverse transcript levels. Docking studies compared binding between cenicriviroc/CCR5 and maraviroc/CCR5.. Unlike maraviroc, cenicriviroc did not cause an increase in the amount of virus present in culture fluids at 4 h compared with baseline. The use of cenicriviroc did, however, result in lower levels of intracellular viral DNA after 4 h. Structural modelling indicates that cenicriviroc binds more deeply than maraviroc to the hydrophobic pocket of CCR5, providing an explanation for the absence of viral rebound with cenicriviroc.. In contrast to maraviroc, cenicriviroc does not repel virus back into extracellular space. Differences in results may be due to superior binding of cenicriviroc to CCR5 compared with maraviroc.

Topics: Anti-HIV Agents; Cell Line; Clinical Trials, Phase II as Topic; Culture Media; DNA, Viral; Enzyme-Linked Immunosorbent Assay; Extracellular Space; HIV Infections; HIV-1; Humans; Imidazoles; Leukocytes, Mononuclear; Real-Time Polymerase Chain Reaction; Sulfoxides; Viral Load; Virus Cultivation

Maraviroc activity against HIV-2, a virus naturally resistant to different HIV-1 antiretroviral drugs, has been recently demonstrated. The aim of this study was to assess HIV-2 susceptibility to cenicriviroc, a novel, once-daily, dual CCR5 and CCR2 antagonist that has completed Phase 2b development in HIV-1 infection.. Cenicriviroc phenotypic activity has been tested using a PBMC phenotypic susceptibility assay against four R5-, one X4- and one dual-tropic HIV-2 clinical primary isolates. All isolates were obtained by co-cultivation of PHA-activated PBMC from distinct HIV-2-infected CCR5-antagonist-naïve patients included in the French HIV-2 cohort and were previously tested for maraviroc susceptibility using the same protocol. HIV-2 tropism was determined by phenotypic assay using Ghost(3) cell lines.. Regarding the 4 R5 HIV-2 clinical isolates tested, effective concentration 50% EC50 for cenicriviroc were 0.03, 0.33, 0.45 and 0.98 nM, similar to those observed with maraviroc: 1.13, 0.58, 0.48 and 0.68 nM, respectively. Maximum percentages of inhibition (MPI) of cenicriviroc were 94, 94, 93 and 98%, similar to those observed with maraviroc (93, 90, 82, 100%, respectively). The dual- and X4-tropic HIV-2 strains were resistant to cenicriviroc with EC50 >1000 nM and MPI at 33% and 4%, respectively.. In this first study assessing HIV-2 susceptibility to cenicriviroc, we observed an in vitro activity against HIV-2 R5-tropic strains similar to that observed with maraviroc. Thus, cenicriviroc may offer a once-daily treatment opportunity in the limited therapeutic arsenal for HIV-2. Clinical studies are warranted.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cells, Cultured; Coculture Techniques; Cyclohexanes; HIV Infections; HIV-2; Humans; Imidazoles; Leukocytes, Mononuclear; Maraviroc; Phenotype; Phytohemagglutinins; Receptors, CCR2; Receptors, CCR5; Sulfoxides; Triazoles; Virus Replication

Treatment of HIV-1-infected individuals is often complicated by the development of antiretroviral resistance, and novel antiretroviral agents with unique mechanisms of action and resistance profiles are needed to address this issue. CCR5 inhibitors represent a new class of antiretroviral agents that block the CCR5 receptor and prevent HIV-1 recognition and entry into CD4+ macrophages and T-cells. Tobira Therapeutics Inc is developing cenicriviroc (TBR-652, formerly TAK-652), a potent inhibitor of CCR5-tropic HIV-1 replication. Cenicriviroc has good oral bioavailability, a long t1/2 that allows once-daily dosing, and has demonstrated excellent antiviral potency with minimal toxicity in in vitro studies and phase I clinical trials. Encouraging efficacy results have been reported from phase II clinical trials in patients with CCR5-tropic HIV-1. The drug is also an inhibitor of the CCR2 receptor, which is known to be associated with inflammatory-related disease states, leading to Tobira initiating a phase I clinical trial in patients with rheumatoid arthritis. Cenicriviroc is a promising CCR5 inhibitor with potentially important anti-inflammatory effects, and warrants further investigation.

Topics: Administration, Oral; Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Drug Combinations; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Imidazoles; Receptors, CCR5; Sulfoxides

TAK-652, a novel small-molecule chemokine receptor antagonist, is a highly potent and selective inhibitor of CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) replication in vitro. Since TAK-652 is orally bioavailable and has favorable pharmacokinetic profiles in humans, it is considered a promising candidate for an entry inhibitor of HIV-1. To investigate the resistance to TAK-652, peripheral blood mononuclear cells were infected with the R5 HIV-1 primary isolate KK and passaged in the presence of escalating concentrations of the compound for more than 1 year. After 67 weeks of cultivation, the escape virus emerged even in the presence of a high concentration of TAK-652. This virus displayed more than 200,000-fold resistance to TAK-652 compared with the wild type. The escape virus appeared to have cross-resistance to the structurally related compound TAK-779 but retained full susceptibility to TAK-220, which is from a different class of CCR5 antagonists. Furthermore, the escape virus was unable to use CXCR4 as a coreceptor. Analysis for Env amino acid sequences of escape viruses at certain points of passage revealed that amino acid changes accumulated with an increasing number of passages. Several amino acid changes not only in the V3 region but also in other Env regions seemed to be required for R5 HIV-1 to acquire complete resistance to TAK-652.

Topics: Amino Acid Sequence; Anti-HIV Agents; CCR5 Receptor Antagonists; Cells, Cultured; Cytopathogenic Effect, Viral; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Imidazoles; Leukocytes, Mononuclear; Molecular Sequence Data; Sulfoxides; Virus Replication