vicriviroc 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

Although HIV has become a treatable disease with near to normal life expectancy, the quest for the development of better tolerated drugs with simple dosing schedules and a high barrier to the emergence of drug resistance remains. Vicriviroc is a small-molecule chemokine receptor antagonist that inhibits the binding of R5-tropic HIV-1 to host cells at the CC-chemokine receptor 5 (CCR5) co-receptor, thus, preventing viral entry. CCR5 inhibitors are believed to possibly decrease inflammation from the immune system and thereby offer additional properties further to their antiretroviral efficacy.. This review is based on a PubMed search covering the years 2005 - 2010 for pharmacokinetic, pharmacological and clinical data of vicriviroc.. In this review, the pharmacokinetic, pharmacological and clinical data of vicriviroc are presented. Moreover, the potential role of vicriviroc in the growing HIV armamentarium is discussed.. Vicriviroc is being developed to be administered in combination with a ritonavir-boosted protease inhibitor for patients with R5-tropic virus. Early clinical trials have established the safety of vicriviroc in both treatment-naive and -experienced R5-tropic HIV-1 infected individuals. Recently, two Phase III clinical trials in treatment-experienced patients failed to prove its superiority over available HIV medications. Phase III trials for treatment-naive patients are still under planning. Clearly, more favorable study results are needed to move vicriviroc into drug registration and approval.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Comorbidity; Drug Interactions; Drug Resistance, Viral; Female; Hepatitis C; HIV Infections; HIV-1; Humans; Male; Piperazines; Pyrimidines

Highly active antiretroviral therapy has revolutionized the care of patients with HIV infection, but treatment is often complicated by the development of antiretroviral resistance. CCR5 inhibitors are a novel class of antiretroviral agents that block the CCR5 receptor, thereby preventing HIV-1 recognition and entry into CD4+ macrophages and T-cells. Schering-Plough Corp is developing vicriviroc, a CCR5 inhibitor that has demonstrated good oral bioavailability, has a long half-life that allows once daily dosing, and is primarily metabolized by cytochrome P450 CYP3A4. In vitro and clinical data suggest that vicriviroc has excellent antiviral potency with minimal toxicity. Phase I and II clinical trials demonstrated promising efficacy results when vicriviroc is administered to patients infected with CCR5-tropic HIV-1. At the time of publication, phase III trials were ongoing or planned to investigate the efficacy and safety of vicriviroc in antiretroviral-naïve and -experienced patients infected with HIV-1.

Topics: Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Piperazines; Pyrimidines

To provide an update on viral entry inhibitors focusing on recently published clinical trials, the routine clinical use of these medications, and future drug candidates.. Clinical trials and cohort studies support the efficacy of both enfuvirtide and maraviroc in the management of treatment-experienced patients. In clinical practice, tolerability issues, particularly injection site reactions, have limited the clinical use of enfuvirtide. Providers should be aware of the need for tropism determination and dosing requirements for maraviroc. The novel chemokine (C-C motif) receptor 5-blocking agent, vicriviroc, has shown promise and is currently in phase III clinical development.. The rapid pace of scientific discovery and pharmaceutical development has led to the release of several novel and well tolerated antiretroviral agents, with activity against resistant isolates. Entry inhibitors remain a critical therapeutic option for treatment-experienced patients. Providers need to be familiar with these agents, and future drug development should be encouraged.

Topics: CCR5 Receptor Antagonists; Cyclohexanes; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Peptide Fragments; Piperazines; Pyrimidines; Salvage Therapy; Triazoles; Virus Internalization

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

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; CCR5 Receptor Antagonists; Fatal Outcome; HIV Infections; Humans; Male; Middle Aged; Piperazines; Pyrimidines; Zygomycosis

CCR5 antagonists are a newly developed class of antiretroviral drugs which inhibit viral entry into the host cell by binding to the predominant HIV coreceptor. Data on the use of these new drugs in treatment-experienced HIV patients are emerging. Clinical trials on maraviroc and vicriviroc in pretreated patients recruited more than 1300 individuals. Interim results of these studies indicate that pretreated patients infected with CCR5-tropic viruses benefit from their use in optimized combination regimens. Maraviroc reduces the HIV-1 viral load in patients with previous triple-class failure by 1.96 log10 copies/ml versus 0.99 log10 copies/ml in placebo; vicriviroc shows potency by dose depending viral decrease of 1.51-1.68 log10 copies/ml compared to 0.29 log10 in placebo. As expected, CCR5 antagonists do not reduce viral load in patients harbouring CXCR4-tropic or dual/mixed tropic viruses. Nevertheless, since a considerable percentage of late-stage HIV patients still bear CCR5-tropic viruses, the use of CCR5 antagonists appears promising in properly selected treatment-experienced patients.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; HIV Infections; HIV-1; Humans; Maraviroc; Piperazines; Pyrimidines; Triazoles

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

HIV CCR5 antagonists select for env gene mutations that enable virus entry via drug-bound coreceptor. To investigate the mechanisms responsible for viral adaptation to drug-bound coreceptor-mediated entry, we studied viral isolates from three participants who developed CCR5 antagonist resistance during treatment with vicriviroc (VCV), an investigational small-molecule CCR5 antagonist. VCV-sensitive and -resistant viruses were isolated from one HIV subtype C- and two subtype B-infected participants; VCV-resistant isolates had mutations in the V3 loop of gp120 and were cross-resistant to TAK-779, an investigational antagonist, and maraviroc (MVC). All three resistant isolates contained a 306P mutation but had variable mutations elsewhere in the V3 stem. We used a virus-cell β-lactamase (BlaM) fusion assay to determine the entry kinetics of recombinant viruses that incorporated full-length VCV-sensitive and -resistant envelopes. VCV-resistant isolates exhibited delayed entry rates in the absence of drug, relative to pretherapy VCV-sensitive isolates. The addition of drug corrected these delays. These findings were generalizable across target cell types with a range of CD4 and CCR5 surface densities and were observed when either population-derived or clonal envelopes were used to construct recombinant viruses. V3 loop mutations alone were sufficient to restore virus entry in the presence of drug, and the accumulation of V3 mutations during VCV therapy led to progressively higher rates of viral entry. We propose that the restoration of pre-CCR5 antagonist therapy HIV entry kinetics drives the selection of V3 loop mutations and may represent a common mechanism that underlies the emergence of CCR5 antagonist resistance.

Topics: Amides; Anti-HIV Agents; CCR5 Receptor Antagonists; Drug Resistance, Viral; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Kinetics; Molecular Sequence Data; Mutation; Piperazines; Pyrimidines; Quaternary Ammonium Compounds; Virus Internalization

We previously described an HIV-1-infected individual who developed resistance to vicriviroc (VCV), an investigational CCR5 antagonist, during 28 weeks of therapy (Tsibris AM et al., J. Virol. 82:8210-8214, 2008). To investigate the decay of VCV resistance mutations, a standard clonal analysis of full-length env (gp160) was performed on plasma HIV-1 samples obtained at week 28 (the time of VCV discontinuation) and at three subsequent time points (weeks 30, 42, and 48). During 132 days, VCV-resistant HIV-1 was replaced by VCV-sensitive viruses whose V3 loop sequences differed from the dominant pretreatment forms. A deep-sequencing analysis showed that the week 48 VCV-sensitive V3 loop form emerged from a preexisting viral variant. Enfuvirtide was added to the antiretroviral regimen at week 30; by week 48, enfuvirtide treatment selected for either the G36D or N43D HR-1 mutation. Growth competition experiments demonstrated that viruses incorporating the dominant week 28 VCV-resistant env were less fit than week 0 viruses in the absence of VCV but more fit than week 48 viruses. This week 48 fitness deficit persisted when G36D was corrected by either site-directed mutagenesis or week 48 gp41 domain swapping. The correction of N43D, in contrast, restored fitness relative to that of week 28, but not week 0, viruses. Virus entry kinetics correlated with observed fitness differences; the slower entry of enfuvirtide-resistant viruses corrected to wild-type rates in the presence of enfuvirtide. These findings suggest that while VCV and enfuvirtide select for resistance mutations in only one env subunit, gp120 and gp41 coevolve to maximize viral fitness under sequential drug selection pressures.

Topics: Anti-HIV Agents; Cell Line; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Peptide Fragments; Phylogeny; Piperazines; Pyrimidines; Virus Internalization; Virus Replication

Vicriviroc, a novel HIV CCR5 antagonist, demonstrated significant efficacy and favorable tolerability in phase II trials in treatment-experienced subjects, supporting further evaluation in phase III studies.. Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic HIV-infected subjects with documented resistance to two antiretroviral classes were conducted. Subjects were randomized to vicriviroc 30 mg QD (N = 571) or PBO (N = 286) with open-label optimized background therapy (OBT) containing ≥2 fully active antiretroviral drugs. The primary endpoint was percentage of subjects with <50 copies/mL HIV RNA at 48 weeks. It was analyzed in a logistic regression with treatment (vicriviroc + OBT/PBO + OBT), use of enfuvirtide in baseline OBT (yes/no), and baseline HIV RNA (≤100,000/>100,000 copies/mL) as covariates. In addition, a pre-planned analysis to examine other efficacy and safety endpoints was conducted.. Baseline characteristics of the pooled mITT population (vicriviroc, n = 486; PBO, n = 235) included mean HIV RNA of 4.6 log(10) copies/mL and mean CD4 count of 257 cells/μL. Approximately 60% of subjects received ≥3 active drugs in the OBT. The percentage of subjects with <50 copies/mL HIV RNA was not significantly different between vicriviroc and PBO at week 48 (64% vs 62%, p = 0.6). However, in subjects receiving ≤2 active drugs in their OBT, the proportion achieving <50 copies/mL HIV RNA was higher in those receiving vicriviroc compared with PBO (70% vs 55%, p = 0.02).. The studies failed to show significant efficacy gains when vicriviroc was added to OBT. However, given the efficacy results of earlier vicriviroc trials and other CCR5 antagonist, studies are needed to define the role of this class of drugs in the treatment of HIV. Clinical trial identifier: http://www.clinicaltrial.gov/: VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370).

Topics: Adult; Anti-HIV Agents; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Piperazines; Placebos; Pyrimidines; Receptors, CCR5; Receptors, HIV; RNA, Viral; Treatment Outcome; Viral Load; Viremia

Vicriviroc is a next-generation antiretroviral compound that blocks HIV from entering uninfected cells by binding to the virus's cellular co-receptor chemokine receptor 5 (CCR5). A potent inhibitor of HIV infection of human cells both in vitro and in vivo, vicriviroc is in development for use in treatment-naïve HIV-1-infected individuals. These patients often receive antiretroviral therapy regimens that include a ritonavir-enhanced protease inhibitor. Such regimens have a high potential for drug-drug interactions because many of the antiretroviral agents inhibit or induce elements of drug elimination pathways, such as the hepatic cytochromes, which may alter drug concentrations and affect both safety and efficacy. The aim of this set of studies was to determine what, if any, dose adjustments or monitoring would be required to use vicriviroc in regimens containing the most common antiretroviral agents.. Drug-drug interactions between vicriviroc and 11 other antiretroviral compounds were investigated in fixed-sequence or parallel-group clinical trials lasting 12-35 days. Fixed-sequence studies were conducted with the protease inhibitors atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, saquinavir and tipranavir. In these studies vicriviroc was administered with ritonavir for a fixed duration, followed by administration of vicriviroc with ritonavir plus the protease inhibitor. Parallel-group studies conducted with lopinavir, zidovudine/lamivudine and tenofovir disoproxil fumarate randomized subjects to receive vicriviroc with or without the study drug. All subjects enrolled in the studies were healthy male and female adults.. The log-transformed data for vicriviroc primary pharmacokinetic parameters on appropriate days were statistically analysed using a one-way analysis of variance (ANOVA) model extracting the effects due to treatment. Steady state was evaluated by an ANOVA model on trough concentrations using day and subject as class variables.. Vicriviroc exposure was not affected by the concurrently administered antiretroviral drugs in any clinically relevant manner, nor did vicriviroc have a clinically relevant effect on the exposure of other drugs. The drug combinations studied were safe and well tolerated, with most adverse events reported as mild to moderate. Aside from the known toxicities of the other antiretroviral drugs, no clinically relevant changes in blood chemistry, haematological parameters, ECGs or vital signs were associated with either vicriviroc or combination treatment.. No dose modification or monitoring of vicriviroc concentrations is necessary when vicriviroc is co-administered with any of the antiretroviral agents reviewed here. The lack of drug-drug interactions suggests that it will be possible to add vicriviroc at the single clinically prescribed dose level to various background regimens that include a boosted protease inhibitor, with all other drugs also prescribed at their standard doses.

Topics: Adolescent; Adult; Anti-Retroviral Agents; Biological Availability; CCR5 Receptor Antagonists; Drug Interactions; Drug Therapy, Combination; Female; Half-Life; HIV Infections; HIV Protease Inhibitors; Human Immunodeficiency Virus Proteins; Humans; Male; Middle Aged; Piperazines; Pyrimidines; Ritonavir; Young Adult

Vicriviroc is a CCR5 antagonist in clinical development for the treatment of HIV-1. Two phase I studies were conducted to assess the safety of vicriviroc. One study characterized the drug's potential to prolong the QT/corrected QT (QTc) interval and to induce arrhythmia. In this partially blind, parallel-group study, 200 healthy subjects aged 18 to 50 years were randomized in equal groups to the following regimens: (i) placebo for 9 days and a single dose of moxifloxacin at 400 mg on day 10, (ii) placebo, (iii) vicriviroc-ritonavir (30 and 100 mg), (iv) vicriviroc-ritonavir (150 and 100 mg), and (v) ritonavir (100 mg). The second study characterized the effects of a range of vicriviroc doses on the central nervous system (CNS). In this third-party-blind, parallel-group study, 30 healthy subjects aged 18 to 48 years were randomized to receive a single dose of either vicriviroc at 200, 250, or 300 mg or placebo, followed by multiple (seven) once-daily doses of either vicriviroc at 150, 200, or 250 mg or placebo, respectively. In the first study, vicriviroc produced no clinically meaningful effect on the QT/QTc interval when administered at a supratherapeutic or therapeutic dose concurrently with ritonavir. In the second study, vicriviroc produced no observable seizure activity, nor was it held to be associated with any clinically relevant changes in brain waveforms in the final consensus of reviewers. These findings showed that vicriviroc produced no clinically relevant QTc prolongation cardiac or epileptogenic effects in healthy individuals at exposures as high as five times those expected for HIV-infected patients receiving therapeutic doses of vicriviroc in a ritonavir-boosted protease inhibitor-containing regimen.

Topics: Adolescent; Adult; Anti-HIV Agents; Arrhythmias, Cardiac; CCR5 Receptor Antagonists; Central Nervous System; Electrocardiography; Electroencephalography; Female; Heart; HIV Infections; Humans; Male; Middle Aged; Piperazines; Pyrimidines; Ritonavir; Young Adult

CCR5 antagonists block HIV cell entry through competitive binding to the CCR5 receptor present on the surface of CD4(+) cells. The CCR5 receptor is also present on CD8(+) cells involved in clearing hepatitis C virus (HCV). The goal of the present study was to examine the short-term safety of a CCR5 antagonist, vicriviroc, in patients with HIV/HCV coinfection.. A randomized, double-blind trial was conducted in 28 HIV/HCV-coinfected subjects with compensated liver disease and plasma HIV RNA below 400 copies/mL. All subjects were receiving a ritonavir-enhanced protease inhibitor regimen, to which vicriviroc (5, 10, or 15 mg/day) or placebo was added for 28 days. Clinical and laboratory evaluations were performed 21 days beyond the treatment period.. Treatment with vicriviroc resulted in no clinically meaningful changes in HCV or HIV viral load or any immune parameters. Adverse events were equally distributed among placebo and vicriviroc groups. Transaminase elevations of grade 1 or more were reported as AEs in 1 subject receiving 10-mg vicriviroc and 1 placebo subject. Vicriviroc plasma concentrations were similar to those observed in healthy subjects.. Short-term treatment with vicriviroc as part of a ritonavir-containing protease inhibitor-based regimen was safe and well tolerated in HIV/HCV-coinfected subjects. HIV/HCV coinfection also did not affect vicriviroc pharmacokinetics.

Topics: Adult; alpha-Fetoproteins; Antigens, CD; Antigens, CD19; Apyrase; C-Reactive Protein; CCR5 Receptor Antagonists; CD4 Antigens; CD4 Lymphocyte Count; CD8 Antigens; Double-Blind Method; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Immunoglobulins; Liver; Lymphocyte Subsets; Male; Middle Aged; Piperazines; Pyrimidines; Viral Load

Agents that block the CCR5 coreceptor for human immunodeficiency virus (HIV) have demonstrated potent antiretroviral activity. In early clinical studies, the CCR5 antagonist vicriviroc proved to be a safe and effective component of combination antiretroviral therapy.. This double-blind, dose-ranging, phase 2 trial randomized subjects to receive 30 mg or 20 mg of vicriviroc or placebo once daily plus re-optimized background therapy containing a protease inhibitor with ritonavir. Subjects were adults infected with CCR5-tropic HIV who were experiencing failure of triple antiretroviral regimens. The primary end point was mean change in baseline log(10) HIV RNA level at 48 weeks, based on an intent-to-treat analysis.. One hundred fourteen persons received vicriviroc at 30 mg (n = 39), vicriviroc at 20 mg (n =40), or placebo (n = 35). The mean change in baseline HIV RNA level at week 48 was -1.77 log(10) copies/mL for 30 mg of vicriviroc and -1.75 log(10) copies/mL for 20 mg of vicriviroc, compared with -0.79 log(10) copies/mL for placebo (P =.002 and P=.003, respectively, compared with placebo). Mean CD4 counts increased by 102, 136, and 63 cells/mm(3) for 30 mg vicriviroc, 20 mg vicriviroc, and placebo, respectively (P = .260 and P = .039, respectively, compared with placebo). Rates of adverse events (mostly mild-to-moderate) were 111.4, 112.5, and 147.4 events per 100 subject-years, respectively.. Vicriviroc administered with a protease inhibitor plus ritonavir-containing regimen shows potent antiretroviral and immunologic activity sustained over 48 weeks in treatment-experienced patients.. NCT00243230 .

Topics: Adult; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Piperazines; Pyrimidines; Ritonavir; RNA, Viral; Viral Load

This substudy of AIDS Clinical Trials Group (ACTG) Protocol 5211 explored the relationship between antiretroviral effect and plasma concentrations of vicriviroc, an investigational CCR5 antagonist for HIV infection.. Eighty-six treatment-experienced subjects failing their current antiretroviral regimens were randomized to add vicriviroc 5, 10, or 15 mg once daily or placebo for 2 weeks. Beyond week 2, subjects were changed to optimized background antiretroviral treatment while continuing vicriviroc or placebo. Plasma samples collected at weeks 2 and 8 were assayed for vicriviroc concentrations and combined with vicriviroc concentration data from 110 seronegatives enrolled in 5 phase 1 studies. An inhibitory Emax model was used to assess pharmacokinetic (PK)/pharmacodynamic relationships and recursive partitioning was applied to determine the breakpoint in vicriviroc PK parameters associated with virologic suppression.. A 2-compartment model was fitted to the drug concentration data. At week 2, a higher vicriviroc Cmin was associated with a greater mean drop in HIV RNA (viral load) and a higher percentage of subjects experiencing a >1 log10 copies/mL drop in viral load. In subjects with Cmin > 54 ng/mL, the mean viral load decrease was 1.35 log10 copies/mL vs. 0.76 log10 with Cmin < 54 ng/mL (P = 0.003, Student t test). At this Cmin breakpoint, 70% of subjects with the higher Cmin had a >1 log drop in HIV RNA, compared with 44% with a lower Cmin (P = 0.048, Fisher exact test). Similar results were seen with an area under the curve breakpoint of 1460 ng h/mL. At weeks 16 and 24, all vicriviroc-treated subjects experienced better viral load responses than placebo recipients, but there was no apparent relationship between PK and change in viral load among these vicriviroc-treated subjects.. There was a positive correlation between vicriviroc Cmin, area under the curve, and viral load changes at week 2 in treatment-experienced HIV-infected subjects receiving no other new active antiretroviral drugs. This correlation did not persist beyond week 16, probably because treatment response at that point also depended on having other active drugs in the regimen.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Area Under Curve; CCR5 Receptor Antagonists; Double-Blind Method; Female; HIV; HIV Infections; Humans; Male; Middle Aged; Nonlinear Dynamics; Piperazines; Pyrimidines; RNA, Viral; Young Adult

Vicriviroc is a C-C motif chemokine receptor 5 (CCR5) antagonist that is in clinical development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This study explored the molecular basis for the development of phenotypically resistant virus.. HIV-1 RNA from treatment-naive subjects who experienced virological failure in a phase 2 dose-finding trial was evaluated for coreceptor usage and susceptibility. For viruses that exhibited reduced susceptibility to vicriviroc, envelope clones were phenotypically and genotypically characterized.. Twenty-six vicriviroc-treated subjects experienced virological failure; for 24 the virus remained CCR5-tropic, and 2 had dual/X4 virus. Reduced susceptibility to vicriviroc, manifested as decreases in the maximum percent inhibition value (no increase in median inhibitory concentration), was detected in 4 of the 26 subjects who experienced virological failure. Clonal analysis of envelopes in samples from these 4 subjects revealed multiple sequence changes in gp160, principally within the variable domain 1/variable domain 2, variable domain 3, and variable domain 4 loops. However, no consistent pattern of mutations was observed across subjects.. In this study, only a small proportion of treatment failures were associated with tropism changes or reduced susceptibility to vicriviroc. Genotypic analysis of cloned env sequences revealed no specific mutational pattern associated with reduced susceptibility to vicriviroc, although numerous changes were observed in the variable domain 3 loop and in other regions of gp160.

Topics: Anti-HIV Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Viral; HIV Envelope Protein gp160; HIV Infections; HIV-1; Humans; Piperazines; Pyrimidines; RNA, Viral; Viral Load

Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity.. Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc.. One hundred eighteen subjects were randomized. Virologic failure (<1 log10 decline in HIV-1 RNA > or =16 weeks postrandomization) occurred by week 48 in 24 of 28 (86%), 12 of 30 (40%), 8 of 30 (27%), 10 of 30 (33%) of subjects randomized to placebo, 5, 10, and 15 mg, respectively. Overall, 113 subjects received vicriviroc at randomization or after virologic failure, and 52 (46%) achieved HIV-1 RNA <50 copies per milliliter within 24 weeks. Through 3 years, 49% of those achieving suppression did not experience confirmed viral rebound. Dual or mixed-tropic HIV-1 was detected in 33 (29%). Vicriviroc resistance (progressive decrease in maximal percentage inhibition on phenotypic testing) was detected in 6 subjects. Nine subjects discontinued vicriviroc due to adverse events.. Vicriviroc seems safe and demonstrates sustained virologic suppression through 3 years of follow-up. Further trials of vicriviroc will establish its clinical utility for the treatment of HIV-1 infection.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Piperazines; Placebos; Pyrimidines; Treatment Outcome; Viral Load

Vicriviroc (VCV) is a CCR5 antagonist with nanomolar activity against human immunodeficiency virus (HIV) replication in vitro and in vivo. We report the results of a phase II dose-finding study of VCV plus dual nucleoside reverse-transcriptase inhibitors (NRTIs) in the treatment-naive HIV-1-infected subjects.. This study was a randomized, double-blind, placebo-controlled trial that began with a 14-day comparison of 3 dosages of VCV with placebo in treatment-naive subjects infected with CCR5-using HIV-1. After 14 days of monotherapy, lamivudine/zidovudine was added to the VCV arms; subjects receiving placebo were treated with efavirenz and lamivudine/zidovudine; the planned treatment duration was 48 weeks.. Ninety-two subjects enrolled. After 14 days of once-daily monotherapy, the mean viral loads decreased from baseline values by 0.07 log(10) copies/mL in the placebo arm, 0.93 log(10) copies/mL in the VCV 25 mg arm, 1.18 log(10) copies/mL in the VCV 50 mg arm, and 1.34 log(10) copies/mL in the VCV 75 mg arm (P < .001 for each VCV arm vs. the placebo arm). The combination-therapy portion of the study was stopped because of increased rates of virologic failure in the VCV 25 mg/day arm (relative hazard [RH], 21.6; 95% confidence interval [CI], 2.8-168.9) and the VCV 50 mg/day arm (RH, 11.7; 95% CI, 1.5-92.9), compared with that in the control arm.. VCV administered with dual NRTIs in treatment-naive subjects with HIV-1 infection had increased rates of virologic failure, compared with efavirenz plus dual NRTIs. No treatment-limiting toxicity was observed. Study of higher doses of VCV as part of combination therapy is warranted.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Piperazines; Pyrimidines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

To determine antiviral activity, pharmacokinetic properties, and safety of vicriviroc, an orally available CCR5 antagonist, as monotherapy in HIV-infected patients.. An ascending, multiple dose, placebo-controlled study randomized within treatment group. Forty-eight HIV-infected individuals were enrolled sequentially to dose groups of vicriviroc: 10, 25 and 50 mg twice a day, and were randomly assigned within group to receive vicriviroc or placebo (16 total patients/group) for 14 days.. Significant reductions from baseline HIV RNA after 14 days were achieved in all active treatment groups. Suppression of viral RNA persisted 2-3 days beyond the end of treatment. Reductions of 1.0 log10 HIV RNA or greater were achieved in 45, 77 and 82% of patients in the three groups, respectively. Eighteen, 46 and 45% of subjects achieved declines of 1.5 log10 or greater in HIV RNA in the three groups, respectively. Vicriviroc was rapidly absorbed with a half-life of 28-33 h, supporting once-daily dosing. Pharmacokinetic parameters were dose linear; steady state was achieved by day 12. Two subjects experienced a transient detectable X4-tropic virus. Vicriviroc was well tolerated in all dose groups. The frequency of adverse events was similar in the vicriviroc and placebo groups: 72 and 62%, respectively. The most frequently reported adverse events included headache, pharyngitis, nausea and abdominal pain, which were not dose related.. Whereas all doses were well tolerated and produced significant declines in plasma HIV RNA, total oral daily doses of 50 or 100 mg vicriviroc monotherapy for 14 days appeared to provide the most potent antiviral effect in this study.

Topics: Administration, Oral; Adolescent; Adult; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Piperazines; Pyrimidines; RNA, Viral; Treatment Outcome; Tropism; Virus Replication

Vicriviroc, an investigational CCR5 inhibitor, demonstrated short-term antiretroviral activity in a phase 1 study.. The present study was a double-blind, randomized phase 2 study of vicriviroc in treatment-experienced, human immunodeficiency virus (HIV)-infected subjects experiencing virologic failure while receiving a ritonavir-containing regimen with an HIV-1 RNA level >or=5000 copies/mL and CCR5-using virus. Vicriviroc at 5, 10, or 15 mg or placebo was added to the failing regimen for 14 days, after which the antiretroviral regimen was optimized. The primary end point was the change in plasma HIV-1 RNA levels at day 14; secondary end points included safety/tolerability and HIV-1 RNA changes at week 24.. One hundred eighteen subjects were randomized with a median HIV-1 RNA level of 36,380 (4.56 log(10)) copies/mL and a median CD4 cell count of 146 cells/mm(3). At 14 days and 24 weeks, mean changes in HIV-1 RNA level (log(10) copies/mL) were greater in the vicriviroc groups (-0.87 and -1.51 [5 mg], -1.15 and -1.86 [10 mg], and -0.92 and -1.68 [15 mg]) than in the placebo group (+0.06 and -0.29) (P<.01). Grade 3/4 adverse events were similar across groups. Malignancies occurred in 6 subjects randomized to vicriviroc and in 2 to placebo.. In HIV-1-infected, treatment-experienced patients, vicriviroc demonstrated potent virologic suppression through 24 weeks. The relationship of vicriviroc to malignancy is uncertain. Further development of vicriviroc in treatment-experienced patients is warranted.

Topics: Adult; Anti-Retroviral Agents; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Piperazines; Pyrimidines; Ritonavir; RNA, Viral; Viral Load

Small-molecule CCR5 inhibitors such as vicriviroc (VVC) and maraviroc (MVC) are allosteric modulators that impair HIV-1 entry by stabilizing a CCR5 conformation that the virus recognizes inefficiently. Viruses resistant to these compounds are able to bind the inhibitor-CCR5 complex while also interacting with the free coreceptor. CCR5 also interacts intracellularly with G proteins, as part of its signal transduction functions, and this process alters its conformation. Here we investigated whether the action of VVC against inhibitor-sensitive and -resistant viruses is affected by whether or not CCR5 is coupled to G proteins such as Gαi. Treating CD4(+) T cells with pertussis toxin to uncouple the Gαi subunit from CCR5 increased the potency of VVC against the sensitive viruses and revealed that VVC-resistant viruses use the inhibitor-bound form of Gαi-coupled CCR5 more efficiently than they use uncoupled CCR5. Supportive evidence was obtained by expressing a signaling-deficient CCR5 mutant with an impaired ability to bind to G proteins, as well as two constitutively active mutants that activate G proteins in the absence of external stimuli. The implication of these various studies is that the association of intracellular domains of CCR5 with the signaling machinery affects the conformation of the external and transmembrane domains and how they interact with small-molecule inhibitors of HIV-1 entry.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; CD4-Positive T-Lymphocytes; Cell Line; Cyclohexanes; Drug Resistance, Viral; env Gene Products, Human Immunodeficiency Virus; GTP-Binding Proteins; HEK293 Cells; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Pertussis Toxin; Piperazines; Pyrimidines; Receptors, CCR5; Transfection; Triazoles

Small molecular CCR5 inhibitors represent a new class of drugs for treating HIV-1 infection. The evaluation of the primary resistance mutations associated with entry inhibitors during HIV-1 perinatal transmission is required because they may have a profound impact on the clinical management in MTCT.. To evaluate the primary resistance mutations to maraviroc and vicriviroc during perinatal transmission and analyze the sensitivity of Env derived from mother-infant pairs to maraviroc.. Nine MIPs infected by subtype C HIV-1 were recruited to analyze the prevalence and transmission of primary resistance mutations to maraviroc and vicriviroc. Moreover, Env derived from six MIPs were employed to construct provirus clones and to analyze the sensitivity to maraviroc.. Mutations A316T, conferring partial resistance to maraviroc, T307I and R315Q, both conferring partial resistance to vicriviroc are prevalent in mother and infant cohorts, indicating the transmission of primary resistance mutations during HIV-1 perinatal transmission. However, the mutations of acutely infected mothers seem to directly transmit to their corresponding infants, while some mutations at low frequency of chronically infected mothers would be lost during transmission. Moreover, provirus clones derived from acutely infected MIPs are less susceptible to maraviroc than those from chronically infected MIPs.. Our study suggests that the transmission mode of primary resistance mutations and the sensitivity to maraviroc are dependent on infection status of MIPs either acutely or chronically infected. These results may indicate that higher dose of maraviroc could be needed for treatment of acutely infected MIPs compared to chronically infected MIPs.

Topics: Adult; Amino Acid Sequence; Cloning, Molecular; Cyclohexanes; Drug Resistance, Viral; env Gene Products, Human Immunodeficiency Virus; Female; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Maraviroc; Molecular Sequence Data; Mutation, Missense; Piperazines; Pregnancy; Pyrimidines; Sequence Analysis, DNA; Triazoles; Young Adult; Zambia

How HIV-1 resistant to small-molecule CCR5 antagonists uses the coreceptor for entry has been studied in a limited number of isolates. We characterized dependence on the N terminus (NT) and the second extracellular loop (ECL2) of CCR5 of three vicriviroc (VCV)-resistant clinical isolates broadly cross-resistant to other CCR5 antagonists. Pseudoviruses were constructed to assess CCR5 use by VCV-sensitive and -resistant envelopes of subtype B and C viruses. We determined the extent of entry inhibition by monoclonal antibodies (MAbs) directed against the NT and ECL2 in the presence and absence of VCV and the capacity of these pseudoviruses to use CCR5 mutants that contained scanning alanine substitutions in the CCR5 NT and ECL2 domains. Sensitive and resistant viruses were completely and competitively inhibited by the ECL2-specific MAb 2D7, whereas the NT-specific MAb CTC5 led to partial noncompetitive inhibition. VCV-resistant clones showed greater sensitivity to 2D7 than VCV-sensitive clones, but in the presence of saturating VCV concentrations, the 2D7 susceptibilities of two VCV-resistant viruses were similar to that of VCV-sensitive virus. The entry of VCV-sensitive and -resistant isolates was impaired to differing degrees by alanine mutations in CCR5; substitutions in NT had the greatest effect on viral entry. HIV-1 clinical isolates broadly resistant to CCR5 antagonists demonstrated significant heterogeneity in their use of CCR5. This heterogeneity makes it difficult to draw general conclusions about the relationship between patterns of CCR5 antagonist resistance and the use of specific CCR5 domains for entry.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; Antibodies, Blocking; Antibodies, Monoclonal; CCR5 Receptor Antagonists; Cyclohexanes; Drug Resistance, Viral; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Piperazines; Pyrimidines; Receptors, CCR5; Triazoles

A rare pathway of HIV-1 resistance to small molecule CCR5 inhibitors such as Vicriviroc (VCV) involves changes solely in the gp41 fusion peptide (FP). Here, we show that the G516V change is critical to VCV resistance in PBMC and TZM-bl cells, although it must be accompanied by either M518V or F519I to have a substantial impact. Modeling VCV inhibition data from the two cell types indicated that G516V allows both double mutants to use VCV-CCR5 complexes for entry. The model further identified F519I as an independent determinant of preference for the unoccupied, high-VCV affinity form of CCR5. From inhibitor-free reversion cultures, we also identified a substitution in the inner domain of gp120, T244A, which appears to counter the resistance phenotype created by the FP substitutions. Examining the interplay of these changes will enhance our understanding of Env complex interactions that influence both HIV-1 entry and resistance to CCR5 inhibitors.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; CCR5 Receptor Antagonists; Cell Line; Drug Resistance, Viral; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; Piperazines; Pyrimidines; Receptors, CCR5; Sequence Alignment

Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop.. To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials.. Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff.. 71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed.. In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility.

Topics: Anti-HIV Agents; Clinical Trials, Phase III as Topic; env Gene Products, Human Immunodeficiency Virus; Genotype; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Phenotype; Piperazines; Pyrimidines; RNA, Viral; Sequence Analysis, DNA; Treatment Failure; Viral Tropism

In the phase 2 VICTOR-E1 study, treatment-experienced subjects receiving 20 mg or 30 mg of the CCR5 antagonist vicriviroc (VCV), with a boosted protease containing optimized background regimen, experienced significantly greater reductions in HIV-1 viral load compared with control subjects. Among the 79 VCV-treated subjects, 15 experienced virologic failure, and of these 5 had VCV-resistant virus. This study investigated the molecular basis for the changes in susceptibility to VCV in these subjects.. Sequence analysis and phenotypic susceptibility testing was performed on envelope clones from VCV-resistant virus. For select clones, an exchange of mutations in the V3 loop was performed between phenotypically resistant clones and the corresponding susceptible clones.. Phenotypic resistance was manifest by reductions in the maximum percent inhibition. Clonal analysis of envelopes from the 5 subjects identified multiple amino acid changes in gp160 that were exclusive to the resistant clones, however, none of the changes were conserved between subjects. Introduction of V3 loop substitutions from the resistant clones into the matched susceptible clones was not sufficient to reproduce the resistant phenotype. Likewise, changing the substitutions in the V3 loops from resistant clones to match susceptible clones only restored susceptibility in 1 clone.. There were no clearly conserved patterns of mutations in gp160 associated with phenotypic resistance to VCV and mutations both within and outside of the V3 loop contributed to the resistance phenotype. These data suggest that genotypic tests for VCV susceptibility may require larger training sets and additional information beyond V3 sequences.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials, Phase II as Topic; Drug Resistance, Viral; HIV Envelope Protein gp160; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Mutation, Missense; Piperazines; Pyrimidines; RNA, Viral; Sequence Analysis, DNA; Treatment Failure

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials, Phase II as Topic; HIV Infections; Humans; Piperazines; Pyrimidines; Receptors, CCR5; Treatment Outcome

Here, we describe the genetic pathways taken by a human immunodeficiency virus type 1 (HIV-1) isolate, D101.12, to become resistant to the small molecule CCR5 inhibitor, vicriviroc (VCV), in vitro. Resistant D101.12 variants contained at least one substitution in the gp120 V3 region (H308P), plus one of two patterns of gp41 sequence changes involving the fusion peptide (FP) and a downstream residue: G514V+V535M or M518V+F519L+V535M. Studies of Env-chimeric and point-substituted viruses in peripheral blood mononuclear cells (PBMC) and TZM-bl cells showed that resistance can arise from the cooperative action of gp120 and gp41 changes, while retaining CCR5 usage. Modeling the VCV inhibition data from the two cell types suggests that D101.12 discriminates between high- and low-VCV affinity forms of CCR5 less than D1/85.16, a resistant virus with three FP substitutions.

Topics: Amino Acid Sequence; Amino Acid Substitution; CCR5 Receptor Antagonists; Drug Resistance, Viral; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; Piperazines; Pyrimidines; Sequence Alignment

Viral reservoirs that persist in HIV-1 infected individuals on antiretroviral therapy (ART) are the major obstacle to viral eradication. The identification and definition of viral reservoirs in patients on ART is needed in order to understand viral persistence and achieve the goal of viral eradication. We examined whether analysis of episomal HIV-1 genomes provided the means to characterize virus that persists during ART and whether it could reveal the virus that contributes to treatment failure in patients on ART. For six individuals in which virus replication was highly suppressed for at least 20 months, proviral and episomal genomes present just prior to rebound were phylogenetically compared to RNA genomes of rebounding virus after therapy interruption. Episomal envelope sequences, but not proviral envelope sequences, were highly similar to sequences in rebounding virus. Since episomes are products of recent infections, the phylogenetic relationships support the conclusion that viral rebound originated from a cryptic viral reservoir. To evaluate whether the reservoir revealed by episomal sequence analysis was of clinical relevance, we examined whether episomal sequences define a viral population that contributes to virologic failure in individuals receiving the CCR5 antagonist, Vicriviroc. Episomal envelope sequences at or near baseline predicted treatment failure due to the presence of X4 or D/M (dual/mixed) viral variants. In patients that did not harbor X4 or D/M viruses, the basis for Vicriviroc treatment failure was indeterminate. Although these samples were obtained from viremic patients, the assay would be applicable to a large percentage of aviremic patients, based on previous studies. Summarily, the results support the use of episomal HIV-1 as an additional or alternative approach to traditional assays to characterize virus that is maintained during long-term, suppressive ART.

Topics: Adolescent; Antiretroviral Therapy, Highly Active; CCR5 Receptor Antagonists; DNA, Complementary; Drug Resistance, Viral; Genome, Viral; HIV Infections; HIV-1; Humans; Phylogeny; Piperazines; Pyrimidines; RNA, Viral; Treatment Failure; Viral Load; Viremia; Virus Replication

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; HIV Infections; Humans; Piperazines; Pyrimidines; Ritonavir; RNA, Viral; Treatment Failure; Viral Load

We previously reported vicriviroc (VCV) resistance in an HIV-infected subject and used deep sequencing and clonal analyses to track the evolution of V3 sequence forms over 28 weeks of therapy. Here, we test the contribution of gp120 mutations to CCR5 antagonist resistance and investigate why certain minority V3 variants emerged as the dominant species under drug pressure.. Nineteen site-directed HIV-1 mutants were generated that contained gp120 VCV resistance mutations. Viral sensitivities to VCV, maraviroc, TAK-779, and HGS004 were determined.. Three patterns of susceptibilities were observed as follows: sigmoid inhibition curves with 50% inhibitory concentration similar to pretreatment virus [07J-week 0 (W0)], single mutants with decreased 50% inhibitory concentrations compared with 07J-W0, and mutants that contained ≥5 of 7 VCV resistance mutations with flattened inhibition curves and decreased or negative percent maximal inhibition. Substitutions such as S306P, which sensitized virus to CCR5 antagonists when present as single mutations, were not detected in the baseline virus population but were necessary for maximal resistance when incorporated into V3 backbones that included preexisting VCV resistance mutations.. CCR5 antagonist resistance was reproduced only when a majority of V3 mutations were present. Minority V3 loop variants may serve as a scaffold upon which additional mutations lead to complete VCV resistance.

Topics: Amides; Amino Acid Sequence; Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; Drug Resistance, Viral; Evolution, Molecular; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Maraviroc; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Peptide Fragments; Piperazines; Pyrimidines; Quaternary Ammonium Compounds; Receptors, CCR5; Triazoles

The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.

Topics: Animals; Anti-HIV Agents; Calcium Signaling; Cell Line; Cells, Cultured; Chemokine CXCL12; CHO Cells; Cricetinae; Cricetulus; Fluorescent Antibody Technique; HIV Infections; HIV-1; Humans; Mice; Mice, SCID; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, CXCR4

HIV-1 variants resistant to small molecule CCR5 inhibitors such as vicriviroc (VVC) have modified Env complexes that can use both the inhibitor-bound and -free forms of the CCR5 co-receptor to enter target cells. However, entry via the inhibitor-CCR5 complex is inefficient in some, but not all, cell types, particularly cell lines engineered to express CCR5. We investigated the effect of increasing CCR5 expression, and hence the density of the inhibitor-CCR5 complex when a saturating inhibitor (VVC) concentration was present, by using 293-Affinofile cells, in which CCR5 expression is up-regulated by the transcriptional activator, ponasterone. When CCR5 expression was low, the resistant virus entered the target cells to a lesser extent when VVC was present than absent. However, at a higher CCR5 level, there was much less entry inhibition at a constant, saturating VVC concentration. We conclude that the relative decrease in entry of a VVC-resistant virus in some cell types results from its less efficient use of the VVC-CCR5 complex, and that increasing the CCR5 expression level can compensate for this inefficiency.

Topics: CCR5 Receptor Antagonists; Cell Line; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Piperazines; Pyrimidines; Receptors, CCR5; Virus Attachment; Virus Internalization

High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000-140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8-2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists.

Topics: Base Sequence; Biological Evolution; CCR5 Receptor Antagonists; Entropy; HIV Infections; HIV-1; Humans; Likelihood Functions; Nucleic Acid Conformation; Piperazines; Pyrimidines; Reproducibility of Results; RNA, Viral; Selection, Genetic; Sequence Alignment; Sequence Analysis, DNA; Time Factors; Treatment Failure

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Maraviroc; Piperazines; Pyrimidines; Pyrrolidinones; Quinolones; Raltegravir Potassium; Succinates; Triazoles; Triterpenes; Viral Load

Despite the availability of 31 antiretroviral agents or fixed-dose combinations in the United States and European Union, there is a continuing need for antiretroviral agents with high genetic barriers to resistance, simple dosing schedules, and favorable tolerability and safety profiles. Vicriviroc is a small-molecule chemokine receptor antagonist that inhibits the binding of R5-tropic HIV-1 to host cells at the CCR5 co-receptor, thus preventing viral entry.. To present an evidence-based assessment of the clinical efficacy, pharmacokinetics, and safety profile of vicriviroc.. We discuss available peer-reviewed publications as well as preliminary data presented at relevant scientific meetings.. Vicriviroc has a favorable pharmacokinetic profile with a half-life that enables once-daily dosing. Minimal drug interactions have been demonstrated with other available antiretrovirals. Early clinical trials have established the safety of vicriviroc in both treatment-naive and treatment-experienced R5-tropic HIV-1 infected individuals. A Phase II study in treatment-experienced patients demonstrated early efficacy of 30 mg vicriviroc in a regimen containing a ritonavir-boosted protease inhibitor (PI/r). Phase III studies using the 30-mg PI/r dosing paradigm in R5-tropic treatment-experienced patients have completed 48 weeks, but data are not yet available. These results will further elucidate the role of vicriviroc in the treatment of HIV-1 infected individuals.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Piperazines; Pyrimidines; Virus Internalization

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials, Phase II as Topic; Double-Blind Method; Drug Therapy, Combination; HIV Infections; Humans; Piperazines; Pyrimidines; Time Factors; Treatment Outcome

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials, Phase II as Topic; HIV Infections; Humans; Piperazines; Pyrimidines

Vicriviroc (VCV) is a chemokine (C-C motif) receptor 5 (CCR5) antagonist with potent anti-HIV activity that currently is being evaluated in phase III clinical trials. In the present study, donor CCR5 density (CCR5 receptors/CD4 lymphocytes) inversely correlated with VCV antiviral activity (Spearman's correlation test; r = 0.746, P = 0.0034). Low doses of the transplant drug rapamycin (RAPA) reduced CCR5 density and enhanced VCV antiviral activity. In drug interaction studies, the RAPA/VCV combination had considerable antiviral synergy (combination indexes of 0.1-0.04) in both multicycle and single-cycle infection of lymphocytes. The synergy between RAPA and VCV translated into dose reduction indexes of 8- to 41-fold reductions for RAPA and 19- to 658-fold reductions for VCV. RAPA enhanced VCV antiviral activity against both B and non-B clade isolates, potently suppressing clade G viruses with reported reduced sensitivities to VCV and to the licensed CCR5 antagonist maraviroc. Importantly, RAPA reduction of CCR5 density in lymphocytes sensitized VCV-resistant strains to VCV, inhibiting virus production by approximately 90%. We further demonstrated the role of CCR5 density on VCV activity against resistant virus in donor lymphocytes and in cell lines expressing varying CCR5 densities. Together, these results suggest that low doses of RAPA may increase the durability of VCV-containing regimens in patients by enhancing VCV viral suppression, by allowing the use of lower doses of VCV with reduced potential for toxicity, and by controlling emerging VCV-resistant variants.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cells, Cultured; Drug Resistance, Viral; Drug Synergism; HIV Infections; HIV-1; Humans; Lymphocytes; Piperazines; Pyrimidines; Sirolimus; Virus Replication

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; HIV; HIV Infections; Humans; Piperazines; Placebos; Pyrimidines; Viral Load

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; HIV Infections; Humans; Piperazines; Pyrimidines; Viral Load

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

Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists. We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004. Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs.

Topics: Amino Acid Sequence; Anti-HIV Agents; Antibodies, Monoclonal; CCR5 Receptor Antagonists; DNA Primers; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Piperazines; Pyrimidines; Receptors, CCR5; Recombination, Genetic; Sequence Homology, Amino Acid; Time Factors; Viral Envelope Proteins

Human immunodeficiency virus type 1 (HIV-1) infection can be inhibited by small molecules that target the CCR5 coreceptor. Here, we describe some properties of clonal viruses resistant to one such inhibitor, SCH-D, using both chimeric, infectious molecular clones and Env-pseudotypes. Studies using combinations of CCR5 ligands, including small molecule inhibitors, monoclonal antibodies (MAbs) and chemokine derivatives such as PSC-RANTES, show that the fully SCH-D-resistant viruses enter target cells by using the SCH-D-bound form of CCR5. However, the way resistance to SCH-D and other small molecule CCR5 inhibitors is manifested depends on the target cell and the nature of the assay (single- vs. multi-cycle). In multi-cycle assays using primary lymphocytes, SCH-D does not inhibit resistant molecular clones, and it can even enhance their infectivity modestly. In contrast, the same viruses (as Env-pseudotypes) are significantly inhibited by SCH-D in single-cycle entry assays using U87-CD4/CCR5 cells, resistance being manifested by incomplete inhibition at high SCH-D concentrations. When a single-cycle, Env-pseudotype entry assay was performed using either U87-CD4/CCR5 cells or PBMC under comparable conditions, entry was inhibited by up to 88% in the former cells but by only 28% in the PBMC. Hence, there are both cell- and assay-dependent influences on how resistance is manifested. We also take this opportunity to correct our previous report that SCH-D-resistant isolates are also substantially cross-resistant to PSC-RANTES [Marozsan, A.J., Kuhmann, S.E., Morgan, T., Herrera, C., Rivera-Troche, E., Xu, S., Baroudy, B.M., Strizki, J., Moore, J.P., 2005. Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D). Virology 338 (1), 182-199]. A substantial element of this resistance was attributable to the unappreciated carry-over of SCH-D from the selection cultures into analytical assays.

Topics: CCR5 Receptor Antagonists; Cells, Cultured; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Piperazines; Pyrimidines; Receptors, CCR5; Virus Replication

A new class of antiretroviral drugs came on the scene in 2003 with the approval of the first entry inhibitor, enfuvirtide (T-20, Fuzeon). Considerable research has been directed toward discovery of additional drugs that target the cell-entry stage of HIV replication, and CCR5 inhibitors--agents that block viral entry via a novel mechanism of action--are poised to join the antiretroviral armamentarium this year.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; HIV Fusion Inhibitors; HIV Infections; Humans; Mutation; Piperazines; Pyrimidines; Receptors, CCR5; Viral Load; Virus Replication

Topics: Anti-HIV Agents; Cyclohexanes; Drug Resistance, Viral; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Lopinavir; Maraviroc; Nitriles; Piperazines; Pyridazines; Pyrimidines; Pyrimidinones; Triazoles

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Drug Approval; HIV Infections; Humans; Piperazines; Pyrimidines

The XVI International AIDS Conference (AIDS 2006), organized by the International AIDS Society (IAS), took place August 12-18 in Toronto, Canada. It was attended by over 26,000 participants from more than 170 countries and featured more than 4,500 abstracts as well as an array of community and cultural activities. The theme of the meeting was "Time to deliver", emphasizing the continued need and urgency in bringing effective HIV prevention and treatment strategies to those living with and affected by HIV/AIDS. The meeting's agenda was broad and included policy and programmatic topics as well as scientific research. This report focuses on reports presented at the conference that directly deal with antiretroviral therapy. This is primarily because of the nature of the venue where it is intended to be published (Drug News & Perspectives) as well as the expertise of the author. It is not a lack of recognition of the other equally important topics and discussions that took place at AIDS 2006. The author is solely responsible for the selection of topics and presentations to be included in this report.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Antibodies, Monoclonal; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Cyclohexanes; Darunavir; Drugs, Investigational; HIV Infections; HIV-1; Humans; Maraviroc; Nitriles; Organic Chemicals; Piperazines; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Receptors, Chemokine; Sulfonamides; Treatment Outcome; Triazoles