Commentary
Human Immunodeficiency Virus (HIV) Entry Inhibitors (CCR5 Specific Blockers) in Development: Are They the Next Novel Therapies? Vincent Idemyor, PharmD Advocate Bethany Hospital, and Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
Since the introduction of the nucleoside reverse transcriptase inhibitor zidovudine in 1987, the number of the available antiretroviral medications has grown to about 20. Despite the efficacy of these medications, treatment-limiting adverse events are frequent. During the last several years, a new class of antiretroviral drugs often referred to as entry inhibitors, specifically the CCR5 blockers, have moved from the basic science laboratories and are now in the clinical phases of drug development. There are three agents in phase 2/3 development that inhibit viral entry by binding to CCR5, disrupting the interaction between the co-receptor and viral glycoprotein (gp) 120. They are aplaviroc (GW-873140), maraviroc (UK-427,857), and vicriviroc (SCH 417690). The development of these new antiviral agents that target different aspects of the viral life cycle is likely to make it possible to suppress viral strains that are resistant to the currently available antiretroviral drugs. There is a growing need for a new class of antiretrovirals with reduced toxicity and improved tolerability. However, currently available information suggests further pharmacokinetics, resistance, safety, and efficacy data are needed to understand how these agents may be effectively used in the clinical setting. Key words: CCR5 inhibitors, HIV-1, viral entry
idovudine, a nucleoside reverse transcriptase inhibitor, was first introduced for treatment of HIV disease in 1987. There are now about 20 licensed antiretroviral medications available for HIV. The currently acceptable standard of care for the treatment of HIV disease is highly active antiretroviral therapy (HAART) involving a combination therapy of at least three antiretroviral medications. HAART continues to reduce the morbidity and mortality associated with HIV infection; however, some individuals experience treatment failure due to tolerability issues and/or development of antiretroviral resistance. Also, these agents have a certain degree of adverse events and drug interactions, thereby limiting the utility of HAART. Because of these reasons, there is an urgent need for new antiviral agents that target enzymes other than reverse transcriptase and viral protease. Many pharmaceutical companies are looking at several stages of the HIV life cycle as
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potential drug targets. The most advanced of these different stages for drug development are agents that interfere with viral entry. RECEPTORS AND THE MECHANISM OF ENTRY The existing antiretroviral drugs prevent the reverse transcriptase enzyme or the protease enzyme, but there are newer classes of compounds in development that inhibit viral entry. They inhibit the initial stage of the virus life cycle. These compounds are attachment inhibitors/blockers, co-re-
For correspondence or reprints contact: Dr. Vincent Idemyor, 5305 South Drexel Avenue, Chicago, Illinois 60615 USA. Email:
[email protected] HIV Clin Trials 2005;6(5):272–277 © 2005 Thomas Land Publishers, Inc. www.thomasland.com
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Figure 1. Components of HIV entry and targets for entry inhibition including co-receptor blockers. There are many different stages of viral entry and each of them is specifically susceptible to antagonism by specific compounds. Reprinted with permission from Dr. Robert W. Doms. Available at: http://clinicaloptions.com. Accessed August 25, 2005.
ceptor inhibitors/blockers, and the fusion inhibitors in which there is one licensed compound. These three classes of entry inhibitor compounds act at different stages of entry, with each compound having a different mechanism of action. The first step in the HIV-1 life cycle is viral attachment to the CD4+ T-cell surface. The next step is viral entry that involves the cascade of molecular interactions between the viral envelope glycoprotein and two T-cell surface receptors – a primary receptor and a co-receptor. The glycoprotein (gp) 120 subunit of HIV enveloped protein first binds to CD4+ T-cell, the primary receptor. This induces a conformational change in the gp120 that allows it to bind to the co-receptor. Co-receptor binding then triggers conformational changes in the gp41 subunit, leading to the insertion of its N-terminal fusion peptide into the host cell membrane. Fusion results in the release of the viral genome into the cytoplasm. Currently, only one licensed compound acts at the fusion stage – the fusion inhibitor enfuvirtide. Enfuvirtide is a peptide of 36 amino acids that binds to HR1 and blocks the snapping together of HR1 and HR2 (Figure 1).
MOLECULAR BASIS OF CO-RECEPTOR TROPISM The co-receptors are members of a large family of G-protein coupling receptors. Although more than a dozen co-receptors have been described, only two co-receptor variants known as CCR5 and CXCR4 are used by all HIV-1 strains. The macrophage-tropic HIV-1 (R5) virus uses CCR5 as a coreceptor during the binding of the gp120 envelope protein to CD4 on a target cell while the T-celltropic HIV-1 (X4 virus) uses the CXCR4 as a coreceptor.1 Initially, HIV-1 strains were categorized by their ability to induce the fusion of infected cells into syncitia forms. The syncitia-inducing (SI) forms are often the X4 viruses, whereas the nonsyncitia inducing (NSI) forms are most often R5 viruses. Currently, co-receptor dependency is no longer defined on the basis of this biology. The concept of co-receptors playing a crucial role became evident in HIV disease when a common mutational variant of CCR5 coding gene known as delta-32 was discovered and seminal papers about the discovery were subsequently published in
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1996.2–5 This 32-nucleotide deletion (delta-32) is within the beta-chemokine receptor 5 (CCR5) gene, and the allele was found to be common in the Caucasian population with a frequency of 0.0808 but was not found in people of Africa or Asian ancestry.5 This CCR5 genetic variant resulted in the production of nonfunctional CCR5 co-receptors. Individuals with two copies of CCR5 delta-32 variant known as delta-32 homozygotes have no functional CCR5 co-receptors and appear to be highly resistant to HIV infection.6 Delta-32 homozygocity appears not to be associated with any significant deleterious effect. Delta-32 heterozygotes inherit one copy of the CCR5 delta-32 variant from one parent and the normal form of the CCR5 gene from the other parent. Delta-32 heterozygotes can become infected with HIV, but the disease progression is significantly delayed compared to those that have two normal copies of the CCR5 gene. HIV strains vary in their ability to use the major co-receptors to achieve entry into the host cell. Some HIV strains use only the CCR5 co-receptors and some use only CXCR4 co-receptors. The strains known as dual-tropic use both CCR5 and CXCR4 co-receptors. Co-receptor selectivity is often determined by genetic sequences within gp120, especially a highly variable and structurally flexible region in the V2 and V3 loops of the gp120 protein.7–9 In the early phase of HIV infection, the virus that uses CCR5 predominates in most individuals; in the late phase of infection, HIV strains capable of using CXCR4 often emerge. Furthermore, changes in co-receptor usage from CCR5 to CXCR4 have been associated with a faster decline of CD4 cells and subsequent progression to acquired immune deficiency syndrome (AIDS). RECEPTOR BLOCKERS A number of compounds known as HIV entry inhibitors are presently in the clinical phases of several trials. HIV entry inhibitors act on a target in the HIV life cycle distinct from the currently approved antiretroviral agents and are of interest because of their activity against multidrug-resistant viruses. The mechanism of action of co-receptor antagonists differs from other available antiretrovirals, because this new class of medications will prevent viral replication by binding to human host cells, such as T-cells and macrophages. These compounds block HIV infection at nanomolar concen-
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trations by binding to a pocket in CCR5 between the transmembrane helices near the extracellular surface. There are three agents in phase 2/3 development that inhibit viral entry by binding to CCR5, thereby disrupting the interaction between the co-receptor and viral gp120. They are aplaviroc (GW-873140), maraviroc (UK-427,857), and vicriviroc (SCH 417690). In monotherapy studies of aplaviroc, involving 40 HIV-infected individuals who were either treatment naïve or off therapy prior to study, entry viral load reductions of 0.46–1.66 log10 copies/mL were observed.10 This was a 10-day study of HIV-infected individuals with R5-tropic virus, a CD4+ lymphocyte count above 200 cells/mm3, and a viral load above 5,000 copies/mL. These individuals were randomized to one of four cohorts: 200 mg every day, 400 mg every day, 200 mg twice a day, or 600 mg twice a day. Each cohort had 10 individuals, with 8 receiving drug and 2 receiving placebo. The percentage of the HIV-infected individuals with a 1 log10 copies/mL drop or greater was 0% in the placebo group, 75% in the 200 mg twice a day, and 100% in the 600 mg twice a day group. Demarest and colleagues11 presented a study designed to assess the anti-HIV activity of aplaviroc against a panel of HIV-1 envelopes from clinical isolates. The samples were collected from treatment-experienced (n = 113) and naïve individuals (n = 299). Analysis of variance (ANOVA) and linear regression methods were used to describe IC50. It was observed that samples from treatment-experienced patients were more susceptible than from naïve patients (p < .0001). CCR5 isolates from latestage HIV-infected individuals tend to be less sensitive than early-stage isolates to CCR5 inhibitors, so the investigation to determine the reasons for the contrary in this study is still being carried out by the authors. However, it was concluded that aplaviroc is active against a broad array of HIV-1 envelopes from treatment-naïve and experienced HIV-infected individuals. Recently, the study arm in naïve patients were stopped due to grade 3/4 liver toxicity, even though the toxicity was an isolated case. We will know more about the toxicity profile of these inhibitors upon completion of the long-term studies. Another study by GlaxoSmithKline (GSK) showed that, after drug withdrawal, significant receptor occupancy of more than 50% prevails for at
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least 5 days.12 Aplaviroc is a novel spirodiketopiperazine CCR5 antagonist with demonstrable potent antiretroviral activity during short-term therapy. It was well tolerated with minor, self-limiting gastrointestinal events such as abdominal cramping, nausea, and loose stools as the most common adverse effect. Adkinson and co-workers13 reported seven-fold increase in the plasma concentration of aplavirioc dose of 400 mg twice a day when combined with lopinavir/ritonavir dose of 400 mg/100 mg twice a day in a pharmacokinetic analysis among healthy volunteers. There are two long-term studies in HIV-infected, treatmentnaïve individuals currently underway, assessing the efficacy and safety of aplaviroc in combination ritonavir-boosted lopinavir and Combivir (lamivudine/zidovudine fixed-dose combination). In a dose-ranging phase 1/2 trial of maraviroc in asymptomatic HIV-infected individuals with CCR5-tropic virus, maraviroc was found to reduce viral load by 1.13 to 1.60 log10 copies/mL in these individuals.14 In this study, 80 individuals infected with CCR5-tropic HIV received one of the several doses of maraviroc, from 25 mg, 100 mg, or 300 mg every day to 50 mg, 100 mg, 150 mg, or 300 mg twice a day. This was compared to placebo for a period of 10 days, and it was noted that CCR5 saturation was achieved by at least 85% with all but the lowest dose studied. In the safety and efficacy data presented by McHale and colleagues15 involving 259 participants including 63 HIV-positive individuals, mean maximum HIV RNA reduction after 10 days of maraviroc 300 mg twice a day monotherapy was 1.84 log10 copies/mL. Sixty-one out of 63 HIV-infected individuals remained CCR5-tropic, whereas the remaining 2 individuals showed emergence of CXCR4 using variants. However, there was no evidence of receptor switch. The safety analysis reported headache, dizziness, nausea, asthenia, flatulence, and rhinitis as the most common treatment-related adverse events. Most of the adverse events were graded as mild or moderate. The authors concluded that maraviroc has a dose-response relationship for both antiviral activity and adverse effects, with the most severe effect of hypotension occurring at total daily doses of 600 mg and higher. Maraviroc is rapidly absorbed with a Tmax of 0.5 to 4.0 hours. The terminal half-life following intravenous dosing is about 13 hours, and administration with food caused approximately 50% reduc-
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tion in systemic exposure at clinically relevant doses. A novel probe study by Muirhead and colleagues16 resulted in a 50% reduction in maraviroc plasma concentration when given with efavirenz, whereas a doubling of drug exposure occurred when it was added to lopinavir-containing regimens. The third CCR5 receptor antagonist in development is vicriviroc. It is a small molecule with a molecular weight of 650 d. The drug is orally bioavailable with a long half-life allowing for oncedaily dosing. In a clinical trial involving 48 HIVpositive individuals with CCR5-tropic virus receiving one of various doses of the vicriviroc from 10 mg, 25 mg, to 50 mg twice a day, the drug was well tolerated when compared to placebo.17 Common adverse events associated with vicriviroc were headache, sore throat, nausea, and abdominal pain. The study was a 14-day, multicenter, randomized, blinded monotherapy trial; within each cohort of 16, 12 patients received active drug and 4 patients received placebo. There was a drop of 0.93 to 1.62 log10 in HIV RNA levels after monotherapy treatment with vicriviroc. The two higher doses had similar effects on virologic suppression and were superior to the 10 mg dose (p = .013). All the HIVinfected individuals were either naïve to antiretroviral therapy or had been off treatment for at least 8 weeks. Saltzman and colleagues recently presented a pharmacokinetics analysis study of vicriviroc, administered alone or in combination with ritonavir or lopinavir/ritonavir.18 Twenty-four healthy participants were randomized to one of three openlabel treatment groups, with one group receiving 10 mg of vicriviroc alone, another group 10 mg of vicriviroc with 100 mg of ritonavir, and the last group receiving 10 mg of vicriviroc with ritonavir 100 mg/lopinavir 400 mg every day for 14 days. The primary end points were Cmax and area under the curve (AUC) analyzed using a one-way ANOVA model with a treatment effect. A significant higher exposure of both Cmax and AUC 0-24 to vicrivroc were observed in the ritonavir or ritonavir/lopinavir groups, and both combinations were well tolerated. On day 14, vicriviroc exposure was boosted significantly by ritonavir/lopinavir with Cmax and AUC 0-24 values of 2.3 and 4.2 times greater, respectively, compared to vicriviroc exposure alone. Two long-term, dose-ranging studies assessing the efficacy of vicriviroc in addition to background antiretrovirals are underway.
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DISCUSSION These available data suggest that the CCR5 receptor blockers will be key tools in the treatment of HIV disease. The pharmacokinetic data for these three products are not entirely straightforward. They are all metabolized by cytochrome P450 enzymes, and the data suggest that the interaction between the CCR5 antagonists and other antiretrovirals will be a clinical challenge for HIV scientists and clinicians. They are metabolized by cytochrome P450 enzyme system pathway, and the AUC and plasma concentrations are decreased by CYP 3A4 inducers such as rifampin and efavirenz. AUC and plasma concentrations are increased by CYP 3A4 inhibitors such as ritonavir. Most of the available data about the efficacy and safety of these CCR5 receptor blockers are from short-term (10–14 days) trials. While these three CCR5 receptor blockers in phase 2/3 development are being discussed, it is worth noting that several co-receptor antagonist compounds, such as SCHC, AMD-3100, ALX 404C, and TAK 779, did not progress through clinical trials and have fallen by the way side. The reasons were either lack of safety or no oral formulation. There are concerns about selection of co-receptor switch mutants, given that these agents do not work against CXCR4-tropic virus. CCR5-specific antagonist will block the entry of R5 viruses, but will blocking one co-receptor drive the virus toward using CXCR4? This is a significant unanswered question, because CXCR4-tropic virus might result in more aggressive disease. The use of co-receptor inhibitors will therefore call for new tests to measure viral tropism, in addition to the viral load and CD4+ lymphocyte count. If administration of the CCR5 receptor blocker cannot decrease HIV-1 RNA load when dual-tropic or CXCR4-using virus is present, then screening assays prior to usage will be necessary. A vectorbased assay for rapid phenotypic assessment of coreceptor usage employing technology based on PhenoSense test is now available.19 There is urgent need to make these assays widely available at reasonable cost to the local institutional laboratories. HIV-1 will certainly acquire resistance to CCR5 inhibitors, and it has already been reported by Trkola and colleagues.20 It is not known how exactly HIV-1 will acquire resistance to CCR5 inhibitors; however, two possibilities are postulated. One
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mechanism by which HIV-1 might acquire resistance to CCR5 inhibitors would be to evolve to use CXCR4. Another mechanism by which HIV-1 might acquire resistance to CCR5 antagonist would be by acquiring mutations in the envelope that enable it to interact with the CCR5 blocker in a way that makes the blocker ineffective. CCR5 exists in different conformations, and there is some variability in how different strains interact with this receptor, providing multiple modes for inhibition of this target. SUMMARY AND CONCLUSION Aplaviroc, maraviroc, or vicriviroc administrations are each associated with a significant level of viral load reduction. There are few observed adverse effects, although long-term studies remain to be done. Questions remain about the potential for the development of resistance, but these CCR5 inhibitors appear to hold promise for significant viral load reductions in the clinical setting. As CCR5 inhibitors progress through clinical trials, we will obtain more information. We will learn how to combine them with existing available products as well as how to incorporate specifics of activity at the molecular level into clinical practice. ACKNOWLEDGMENTS I appreciate the thoughtful contributions of Joe Groosman, MSW.
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14. Fatkenheuer G, Pozniak AL, Johnson M, et al. Evaluation of dosing frequency and food effect on viral load reduction during short-term monotherapy with UK-427,857 a novel CCR5 antagonist. In: Program and abstracts of the 15th International AIDS Conference; 2004; Bangkok, Thailand. Abstract TuPeB4489. 15. McHale M, Abel S, Russell D, et al. Overview of phase 1 and 2a safety and efficacy data of maraviroc (UK-427,857). In: Program and abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005; Rio de Janeiro, Brazil. Abstract Tuoa0204. 16. Muirhead G, Pozniak A, Gazzard B, et al. A novel probe drug interaction study to investigate the effect of selected ARV combinations on the pharmacokinetics of a single oral dose of UK-427,857 in HIV+ ve subjects. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; 2005; Boston, MA. Abstract 663. 17. Schuermann D, Pechardscheck C, Rouzier R, et al. SCH 417690: antiviral activity of a potent new CCR5 receptor antagonist. In: Program and abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005; Rio de Janeiro, Brazil. Abstract TuOa0205. 18. Saltzman M, Rosenberg M, Kraan M, et al. Pharmacokinetics of SCH 417690 administered alone or in combination with ritonavir or lopinavir/ritonavir. In: Program and abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005; Rio de Janeiro, Brazil. Abstract TuPe3.1B05. 19. Moyle G, Lalezari J. Blocking viral entry. J Viral Entry. 2005;1(1):2–3. 20. Trkola A, Kuhmann SE, Strizki JM, et al. HIV-1 escape from a small molecule, CCR5 specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci USA. 2002;99:395– 400.
