aplaviroc 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

Viral entry is an early stage and specific of the infection in which different viral and cellular targets are accessible to therapeutic treatment. CXCR4 and CCR5 act in this process as coreceptor molecules of HIV for its entry into the host cell. The predominant role played by the CCR5 coreceptor in the transmission and spreading of HIV makes this molecule the target of choice for blocking this mechanism. In the last few years, different specific inhibitors of HIV coreceptors have been generated of which only one, Maraviroc, has been approved for clinical use. The synthetic inhibitors developed act as allosteric antagonists that induce a non-permissive state or configuration of the coreceptor for binding viral envelope-glycoproteins. The CCR5 antagonists act on a wide spectrum of viruses with affinity or tropism for this receptor (virus R5), are absorbed orally and have powerful antiviral activity. However, the optimistic perspective offered by these new molecules has to be moderated due to the possible and expected appearance of viral resistances, on the one hand, and the propagation of viral species with affinity or tropism for the CXCR4 receptor (virus X4). This situation is a reality verified in the first clinical trials with these drugs and they acutely and urgently show the need to have effective and non-toxic CXCR4 inhibitors available to block this alternative viral replication and escape route.

Topics: Adult; Amides; Benzoates; CCR5 Receptor Antagonists; CD4 Antigens; Chemokines, CC; Chemokines, CXC; Clinical Trials as Topic; Cyclohexanes; Diketopiperazines; Drug Design; env Gene Products, Human Immunodeficiency Virus; HIV; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Membrane Fusion; Models, Molecular; Piperazines; Pyrimidines; Quaternary Ammonium Compounds; Receptors, CCR5; Receptors, CXCR4; Spiro Compounds; Structure-Activity Relationship; Triazoles; Virus Attachment; Virus Internalization

Maraviroc is the first inhibitor of CCR5 co-receptors to be marketed as an antiretroviral. The pre-clinical studies and phase III trials have shown that it has a very favourable safety profile. No characteristic adverse effect of maraviroc has been identified. Unlike with aplaviroc, where its clinical development was stopped due to serious hepatoxicity, no increase in liver toxicity has been demonstrated in patients treated with maraviroc even if they are co-infected by hepatotropic virus. Nor was there any evidence of an increase in the incidence of neoplasms or serious infections in patients treated with maraviroc. In a study on naive patients, maraviroc produced nonsignificant changes in total cholesterol, LDL, HDL and triglycerides. Although CCR5 co-receptors play a role in the immune response of the body, it has not been shown whether individuals homozygote for its deletion (delta-32 mutation) have an increased risk of serious infections, with the possible exception of encephalitis due to the West Nile virus. However, long-term follow up is required on patients treated with to be able to rule out any increased susceptibility to infections or neoplasms.

Topics: Adult; Benzoates; CCR5 Receptor Antagonists; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Comorbidity; Cyclohexanes; Diketopiperazines; Disease Susceptibility; Drug Design; env Gene Products, Human Immunodeficiency Virus; HIV Fusion Inhibitors; HIV Infections; Homozygote; Humans; Hyperlipidemias; Incidence; Infections; Maraviroc; Membrane Fusion; Neoplasms; Piperazines; Receptors, CCR5; Sequence Deletion; Spiro Compounds; Triazoles; Virus Attachment; Virus Internalization

A new class of antiretroviral drugs is now available to the HIV provider: The CCR5 Antagonists belong to a group of entry inhibitors with a novel mechanism of action. While these antagonists do not directly interfere with any of the steps of HIV replication, they block the CCR5 receptor, one of the co-receptors HIV uses to enter its target cell. Thus CCR5 antagonists are able to prevent infection of the cell and represent a new and unique mechanism for the treatment of HIV. There is great interest in utilizing this new drug class in early treatment of HIV to prevent infection of large cell pools; CCR5 antagonists even may be useful tools in the various settings of exposure prophylaxis. Maraviroc is now approved in both the European Union and the United States for the treatment of HIV infection. This is the first medication belonging to the new class of CCR5 antagonists, and the first approval of an orally available drug in a new class since 1996. Aplaviroc, maraviroc, and vicriviroc are small molecule inhibitors of CCR5 that block HIV-1 infection in vitro and reduce plasma HIV-1 RNA in HIV infected subjects by approximately 1.5 log10 copies/mL over 10-14 days when given as single agents. Very limited data is available on the use of CCR5 antagonists in treatment naive patients due to early termination of many trials because of inferior performance or toxicity and at the time of this writing in August 2007 there is only one ongoing non-inferiority trial in the naive patient population. The 48 week interim results of this trial using twice daily maraviroc were reported at the International AIDS Society meeting in July 2007. Maraviroc compared to efavirenz was non-inferior in regards to percentage of subjects reaching viral loads below 400 copies/mL, but not so for the analysis of subjects reaching viral loads below 50 copies/mL. On the other hand maraviroc had a superior side-effect profile, fewer adverse events and a greater increase of CD4 cell count than efavirenz. These data will revitalize the interest in CCR5 antagonists as a treatment option for the treatment-naive patients. In order to be used as first line drugs, CCR5 antagonists face a number of challenges: They will have to be proven to be as potent, durable, safe, and convenient as current available options. Important questions unique to this new class will have to be answered: What are the mechanisms and risks of tropism change? What is the role and needed frequency of tropism testing, and what

Topics: Adolescent; Adult; Anti-HIV Agents; Benzoates; CCR5 Receptor Antagonists; Cyclohexanes; Diketopiperazines; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Piperazines; Pyrimidines; Randomized Controlled Trials as Topic; Spiro Compounds; Triazoles

Topics: Benzoates; CCR5 Receptor Antagonists; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Cyclohexanes; Diketopiperazines; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Piperazines; Pyrimidines; Spiro Compounds; Treatment Outcome; Triazoles

Human immunodeficiency virus (HIV) is a retrovirus that is the causative agent of acquired immunodeficiency syndrome (AIDS). Current HIV therapy is based on targeting two critical enzymes in the viral replication machinery: reverse transcriptase and a virally encoded protease. Although mortality rates due to HIV infection have been dramatically reduced, AIDS remains a major health problem throughout the world. The emergence of HIV variants that are resistant to current therapies and potential toxicity associated with their chronic use has highlighted the need for new approaches to HIV inhibition. Identification of the mechanisms underlying viral entry into the host cell has provided a number of novel therapeutic targets and the first of these HIV fusion inhibitors (enfuvirtide [pentafuside, T-20, Fuzeon; Roche Laboratories and Trimeris]) has recently been approved in the US and Europe. This review will focus on recent progress in the development of therapeutics that target the HIV entry process.

Topics: Amino Acid Motifs; Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Antigens; Clinical Trials as Topic; Cyclic N-Oxides; Dogs; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Haplorhini; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Membrane Fusion; Membrane Glycoproteins; Organic Chemicals; Oximes; Peptide Fragments; Piperazines; Piperidines; Protein Binding; Pyridines; Pyrimidines; Rabbits; Receptors, CCR5; Receptors, CXCR4; Reverse Transcriptase Inhibitors; Spiro Compounds

The CCR102881 (ASCENT) study evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc plus a fixed-dose combination of lamivudine-zidovudine (Combivir) in drug-naïve human immunodeficiency virus type 1-infected subjects with only CCR5-tropic virus detected in plasma. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight subjects met protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma at baseline and at the time of virologic failure. Molecular evolutionary analyses were also performed. The majority of the subjects with virologic failure (six of eight) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to aplaviroc at the time of virologic failure, even at the clonal level. Six subjects with virologic failure maintained CCR5 tropism, while two exhibited a change in population tropism readout to dual/mixed-tropic with R5X4-tropic clones detected prior to therapy. Two evolutionary patterns were observed: five subjects had no evidence of population turnover, while three subjects had multiple lines of evidence for env population turnover. The acquisition of the M184V mutation is the primary characteristic of virologic failure in first-line therapy with aplaviroc plus lamivudine-zidovudine, regardless of the envelope tropism.

Topics: Anti-HIV Agents; Benzoates; Diketopiperazines; Drug Combinations; Drug Resistance, Viral; env Gene Products, Human Immunodeficiency Virus; HIV Infections; HIV-1; Humans; Lamivudine; Phylogeny; Piperazines; Receptors, CCR5; Reverse Transcriptase Inhibitors; Spiro Compounds; Treatment Failure; Tropism; Zidovudine

This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral-naïve patients harbouring R5- or R5X4-tropic virus.. A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed.. This study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability.. While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.

Topics: Adult; Aged; Benzoates; Diketopiperazines; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Piperazines; Pyrimidinones; Receptors, CCR5; Ritonavir; RNA, Viral; Spiro Compounds; Young Adult

Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naïve, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.

Topics: Adult; Alanine Transaminase; Benzoates; Bilirubin; Chemical and Drug Induced Liver Injury; Diketopiperazines; Double-Blind Method; Female; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Liver; Male; Piperazines; Spiro Compounds

Aplaviroc (GW873140) binds specifically to human cellular CC chemokine receptor 5 (CCR5) and demonstrates potent anti-human immunodeficiency virus activity in vitro in the subnanomolar range. In vitro studies show that aplaviroc selectively inhibits the binding of a particular monoclonal antibody, 45531, to CCR5. Based on this observation, a flow cytometry-based assay was developed to determine percentage CCR5 receptor occupancy (RO). CCR5 receptor occupancy was aplaviroc concentration-dependent and related to anti-human immunodeficiency virus activity in vitro. In the clinical setting, CCR5 receptor occupancy in peripheral blood was >98% in all subjects within 2 to 3 hours of dosing, which is consistent with the peak plasma concentrations of drug. Longitudinal analysis in the drug washout period revealed the time to 50% CCR5 receptor occupancy averaged >100 hours, in both human immunodeficiency virus-positive and human immunodeficiency virus-negative subjects, substantially longer than the plasma pharmacokinetic half-life of 3 hours. The duration of CCR5 receptor occupancy appeared to be dose-dependent and associated with antiviral activity as measured by plasma human immunodeficiency virus RNA nadir following 10 days of multiple dose administration. These data demonstrate that the analysis of CCR5 receptor occupancy, in addition to conventional plasma-based pharmacokinetic measures, provides an informative tool to assist in evaluating the pharmacodynamic and antiviral effects of cellular CC chemokine receptor antagonists.

Topics: Adult; Antibodies, Monoclonal; Benzoates; Diketopiperazines; Dose-Response Relationship, Drug; Double-Blind Method; Female; Flow Cytometry; Half-Life; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Piperazines; Protein Binding; Receptors, CCR5; RNA, Viral; Spiro Compounds; Time Factors; Young Adult

This Phase IIb study explored the antiviral activity and safety of the investigational CCR5 antagonist aplaviroc (APL) in antiretroviral-naive patients harbouring R5-tropic virus.. One hundred and forty-seven patients were randomized 2:2:1 to one of two APL dosing regimens or efavirenz (EFV). All dosage arms were administered twice daily and in combination with lamivudine/zidovudine (3TC/ZDV; Combivir, COM). Efficacy, safety, and pharmacokinetic parameters were assessed.. This study was prematurely terminated due to APL-associated idiosyncratic hepatotoxicity. The primary endpoint of the study was the proportion of patients with plasma HIV-1 RNA <400 copies/ml who remained on randomized treatment through week 12. Of the 147 patients enrolled, 145 patients received one dose of treatment and were included in the intention-to-treat population. The proportion of patients with HIV-1 RNA <400 copies/ml at week 12 was 53%, 50% and 66% in the APL 600 mg twice daily, APL 800 mg twice daily, and EFV arms, respectively. Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated non-linear pharmacokinetics with high interpatient variability. In addition to the hepatic findings, there was an apparent dose-response relationship in the incidence of diarrhoea.. Whereas target plasma concentrations of APL were achieved, the antiviral activity of APL as the third agent in a triple drug regimen did not appear to be comparable to EFV in this treatment-naive patient population.

Topics: Adult; Aged; Anti-HIV Agents; Benzoates; Diketopiperazines; Double-Blind Method; Drug Therapy, Combination; Female; HIV Fusion Inhibitors; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Piperazines; Reverse Transcriptase Inhibitors; Spiro Compounds; Treatment Outcome; Zidovudine

873140 is a spirodiketopiperazine CCR5 antagonist with prolonged receptor binding and potent antiviral activity in vitro. This study evaluated plasma HIV RNA, safety, and pharmacokinetics following short-term monotherapy in HIV-infected adults.. Double-blind, randomized, placebo-controlled multi-center trial.. Treatment-naive or experienced HIV-infected subjects with R5-tropic virus, CD4 cell count nadir > 200 x 10 cells/l, viral load > 5000 copies/ml and not receiving antiretroviral therapy for the preceding 12 weeks were enrolled. Forty subjects were randomized to one of four cohorts (200 mg QD, 200 mg BID, 400 mg QD, 600 mg BID) with 10 subjects (eight active, two placebo) in each cohort, and received treatment for 10 days. Serial HIV RNA, pharmacokinetics, and safety evaluations were performed through day 24.. Of the 40 subjects, 21 were treatment-experienced; 35 were male, 20 were non-white, and eight were coinfected with hepatitis C virus. Median baseline HIV RNA ranged from 4.26 log10 to 4.46 log10. 873140 was generally well tolerated with no drug-related discontinuations. The most common adverse events were grade 1 gastrointestinal complaints that generally resolved within 1-3 days on therapy. No clinically significant abnormalities were observed on electrocardiogram or in laboratory parameters. Mean log changes in HIV RNA at nadir, and the percentage of subjects with > 1 log10 decrease were -0.12 (0%) for placebo, -0.46 (17%) for 200 mg once daily, -1.23 (75%) for 200 mg twice daily, -1.03 (63%) for 400 mg once daily, and -1.66 (100%) for 600 mg twice daily. An Emax relationship was observed between the area under the 873140 plasma concentration-time curve and change in HIV RNA.. 873140 demonstrated potent antiretroviral activity and was well tolerated. These results support further evaluation in Phase 2b/3 studies.

Topics: Adult; Anti-HIV Agents; Benzoates; CCR5 Receptor Antagonists; Diketopiperazines; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Piperazines; RNA, Viral; Spiro Compounds; Treatment Outcome

Broadly neutralizing antibodies PG9 and PG16 effectively neutralize 70 to 80% of circulating HIV-1 isolates. In this study, the neutralization abilities of PG9 and PG16 were further enhanced by bioconjugation with aplaviroc, a small-molecule inhibitor of virus entry into host cells. A novel air-stable diazonium hexafluorophosphate reagent that allows for rapid, tyrosine-selective functionalization of proteins and antibodies under mild conditions was used to prepare a series of aplaviroc-conjugated antibodies, including b12, 2G12, PG9, PG16, and CD4-IgG. The conjugated antibodies blocked HIV-1 entry through two mechanisms: by binding to the virus itself and by blocking the CCR5 receptor on host cells. Chemical modification did not significantly alter the potency of the parent antibodies against nonresistant HIV-1 strains. Conjugation did not alter the pharmacokinetics of a model IgG in blood. The PG9-aplaviroc conjugate was tested against a panel of 117 HIV-1 strains and was found to neutralize 100% of the viruses. PG9-aplaviroc conjugate IC50s were lower than those of PG9 in neutralization studies of 36 of the 117 HIV-1 strains. These results support this new approach to bispecific antibodies and offer a potential new strategy for combining HIV-1 therapies.

Topics: Antibodies, Neutralizing; Benzoates; CD4 Immunoadhesins; Cell Line; Diketopiperazines; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunoconjugates; Neutralization Tests; Piperazines; Spiro Compounds; Virus Internalization

CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals.

Topics: Benzoates; Cell Line; Cells, Cultured; Diketopiperazines; Drug Resistance, Viral; env Gene Products, Human Immunodeficiency Virus; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Mutation, Missense; Piperazines; Receptors, HIV; Sequence Analysis, DNA; Spiro Compounds; Virus Internalization

HIV-1 utilizes CD4 and either chemokine (C-C motif) receptor 5 (CCR5) or chemokine (C-X-C motif) receptor 4 (CXCR4) to gain entry into host cells. Small molecule CCR5 antagonists are currently being developed for the treatment of HIV-1 infection. Because HIV-1 may also use CXCR4 for entry, the use of CCR5 entry inhibitors is controversial for patients harboring CCR5-using and CXCR4-using (dual/mixed-tropic) viruses. The goal of the present study was to determine the proportion of CCR5-tropic and CXCR4-tropic viruses in dual/mixed-tropic virus isolates from drug-naïve patients and the phenotypic and genotypic relationships of viruses that use CCR5 or CXCR4 or both.. Fourteen antiretroviral-naive HIV-1-infected patients were identified as having population coreceptor tropism readout of dual/mixed-tropic viruses. Intrapatient comparisons of coreceptor tropism and genotype of env clones were conducted on plasma virus from each patient.. Population HIV-1 envelope tropism and susceptibility to the CCR5 entry inhibitor, aplaviroc, were performed using the Monogram Biosciences Trofile Assay. Twelve env clones from each patient were analyzed for coreceptor tropism, aplaviroc sensitivity, genotype, and intrapatient phylogenetic relationships.. Viral populations from antiretroviral-naive patients with dual/mixed-tropic virus are composed primarily of CCR5-tropic env clones mixed with those that use both coreceptors (R5X4-tropic) and, occasionally, CXCR4-tropic env clones. Interestingly, the efficiency of CXCR4 use by R5X4-tropic env clones varied with their genetic relationships to CCR5-tropic env clones from the same patient.. These data show that the majority of viruses in these dual/mixed-tropic populations use CCR5 and suggest that antiretroviral-naive patients may benefit from combination therapy that includes CCR5 entry inhibitors.

Topics: Benzoates; CD4 Lymphocyte Count; Cells, Cultured; Diketopiperazines; Drug Resistance, Viral; env Gene Products, Human Immunodeficiency Virus; Evolution, Molecular; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Phylogeny; Piperazines; Receptors, CCR5; Receptors, CXCR4; RNA, Viral; Spiro Compounds; Tropism

Inhibition of CCR5 co-receptor which is also a chemokine receptor, is a new way for inhibition of HIV-1 replication. Small antagonist molecules exert non competitive inhibition of the HIV co-receptor CCR5, which is essential for HIV entry. The CCR5 antagonists aplaviroc (GlaxoSmithKine), vicriviroc (Schering-Plough), and maraviroc (Pfizer) have reached phases III of clinical development. The development of aplaviroc was stopped because of its hepatotoxicity in some of the HIV-infected patients. In ACTG 5211 and MOTIVATE trials, treatment-experienced subjects who added respectively vicriviroc and maraviroc demonstrated substantially greater reductions in plasma HIV-1 RNA levels than those who received the placebo ; maraviroc currently having obtained European authorization. The place of this new class in the strategies of initial, switch or rescue treatment remains to be clarified. The limitations of the use of these small molecules depend on their mechanism of action : obligation for monitoring the evolution of coreceptor usage, risk of failure by emergence of pre-existing strains with CXCR4 (X4) tropism or by resistant strains with CCR5 tropism, potential risks related to blocking of the physiological functions of this chemokine receptor.

Topics: Benzoates; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Diketopiperazines; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Piperazines; Pyrimidines; Spiro Compounds; Triazoles

This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects.. In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg + LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2.. In Part 1, a single RTV dose increased the APL AUC(0-infinity) by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, C(max), and C(min), respectively. No change in LPV AUC or C(max) and a small increase in RTV AUC and C(max) (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported.. Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.

Topics: Adolescent; Adult; Animals; Benzoates; CCR5 Receptor Antagonists; Diketopiperazines; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Male; Mice; Middle Aged; Piperazines; Pyrimidinones; Rats; Ritonavir; Spiro Compounds

Topics: Anti-HIV Agents; Benzoates; Controlled Clinical Trials as Topic; Diketopiperazines; Drug Approval; HIV; HIV Infections; Humans; Piperazines; Spiro Compounds; United States; United States Food and Drug Administration; Viral Load