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Antiretroviral agents that inhibit CCR5-utilizing HIV-1
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Eric S. Daar, M.D.
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine David Geffen School of Medicine at UCLA
Address: Division of HIV Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA 90502
Introduction
The past 10 years has witnessed the development of multiple new antiretroviral agents in existing and novel classes. This includes several nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors and protease inhibitors. Many of the newer drugs in these classes have been developed to have activity against viruses resistant to earlier generations of drugs in the class. The first new drug in a new class since PIs was the fusion inhibitor enfuvirtide approved by the Food and Drug Administration (FDA) in 2003 for treatment-experienced patients. The search for other new drugs in novel classes has recently resulted in the approval of an integrase inhibitor and CCR5 antagonist. The latter represents a triumph in drug development but brings with it unique complexity for clinicians and patients.
Shortly after the discovery of HIV-1 as the causative agent of AIDS it was clear that the primary cellular receptor for the virus was CD4. Approximately 10 years later investigators identified the seven transmembrane chemokine receptors CCR5 and CXCR4 which act as coreceptors for HIV-1 entry. The majority of strains of HIV-1 identified during the first weeks and years of infection use CCR5, and then over time approximately 50% of patients will have viruses that are CXCR4 1, 2. The identification of chemokine coreceptors led to research into HIV-1 pathogenesis and the search for drugs that would target this step in the viral life cycle, ultimately resulting in the approval of the CCR5 antagonist maraviroc.
Unique concerns for the CCR5 antagonist class relate to the fact that this is the first antiviral drug to target the cell, yet alone interact with a molecule important for coordinating host immune responses. Reassurance comes from the fact that approximately 1% of Caucasians is born with two mutated CCR5 genes and lack CCR5 expression on the surface of their cells 3, 4. Furthermore, these people appear to lead relatively normal lives without overt evidence of immunologic deficits. While this suggests that pharmacologic inhibition of CCR5 may not be detrimental, those born without a part of the immune system may develop immunologic redundancy not present in those that have this molecule blocked in adulthood. In addition, there is evidence that these people with mutated CCR5 genes may be at increased risk for select infections, such as severe West Nile Virus 5. Another unique concern regarding CCR5 inhibition is that viruses may emerge on therapy able to use the CXCR4 coreceptor. While cause and effect has not been established, several natural history studies demonstrate that the presence of CXCR4-using HIV-1 is associated with rapid disease progression 6, 7.
Clinical data
Maraviroc was approved for treatment-experienced patients without detectable CXCR4-using virus. Two pivotal phase 3 trials showed significantly better virologic responses in those who received the drug with optimized background therapy than those who received optimized background regimen alone. There was also no apparent difference in safety, including rate of infections or malignancies amongst those who received maraviroc compared to the control group. While more than half of the patients had CXCR4-using virus at the time of virologic failure there was no evidence that this was associated with HIV-1 disease progression 8. Studies with another CCR5 antagonist, vicriviroc in treatment-experienced patients has shown similar safety and efficacy 9.
Clinical trials have also been performed using CCR5 antagonists with dual NRTIs in treatment-naive patients. A Phase 2b study with vicriviroc showed increased risk of virologic failures at the lower doses resulting in the study being prematurely stopped with further consideration of optimal dosing 10. A phase 3 trial in treatment-naive patients treated with dual NRTIs with either maraviroc or efavirenz showed very similar efficacy but was unable to demonstrate that maraviroc was non inferior to the comparator arm 11. Further analyses of this study as well as those in treatment-experienced patients provide evidence that the sensitivity of the phenotypic tropism assay to detect low levels of CXCR4-using virus may be clinically relevant. In fact, all studies have shown a small percentage of those initially screened to have no detectable CXCR4-using virus did have such viruses detected at baseline before receiving a CCR5 antagonist. Moreover, those who had CXCR4-using virus identified at baseline were at higher risk for experiencing virologic failure. As a result of this the phenotypic assay has been modified to have enhanced sensitivity for detecting CXCR4-using virus 12. A retrospective analysis used the new assay on specimens from the screening visit of the treatment-naive trial with maraviroc. When those with CXCR4-using virus detected by the enhanced assay were excluded from the analysis the response rates between study arms were virtually identical with less rash, neurologic symptoms and lipid changes in the maraviroc group 13.
In order to further address the concerns of selecting or enriching for a CXCR4-using viral population a phase 2b safety study was performed in those who were screened to have CXCR4-using virus. There was no apparent difference in virologic response amongst those given maraviroc with an optimized background versus optimized background alone 14, although there was a trend toward greater increase in CD4+ T-cells in the maraviroc-treated patients.
Another novel approach to blocking CCR5 is with the use of monoclonal antibodies. PRO 140 is a humanized monoclonal antibody that interacts with CCR5 and prevents infection by viruses that utilize this receptor. Early data has demonstrated short term reductions in plasma HIV-1 RNA in patients treated with this drug intravenously and more recently by subcutaneous administration 15. Further safety and efficacy data will come from larger trials of patients without detectable CXCR4-using virus.
Unique issues for these agents
It is clear from our understanding of how CCR5 antagonists work that there are unique issues that need to be fully understood by both clinicians and patients. This includes the fact that screening must be performed for CXCR4-using virus prior to their use. Moreover, there are potential unique concerns when using a drug that targets a cell receptor that plays a role in the immune response.
Coreceptor tropism testing
Maraviroc is currently the only FDA-approved drug that blocks HIV-1 infection via the CCR5 coreceptor and is approved for those who are treatment-experienced with no detectable CXCR4-using virus. In all likelihood similar screening will be required for all drugs in development that act at this step in the viral life cycle. The need for tropism testing has introduced numerous novel issues for clinicians. First of all, several studies have shown that in the advanced stages of disease approximately 50% of patients will prove ineligible for this therapy due to the presence of detectable CXC4-using virus 2, 16, 17. In addition, the one phenotypic assay validated in most of the recently performed studies is relatively expensive, takes several weeks to report results and occasionally may not be able to report any result 18. Even more importantly early studies showed that there were individuals that did not initially have detectable CXCR4-using virus that were in fact there at low levels and when present associated with the drug having less or possibly no antiviral activity. This was a significant concern for clinicians who would be depending upon the activity of the CCR5 antagonist to maximize the chance of achieving full virologic suppression and avoid the emergence of resistance to other drugs being utilized in the new regimen. This issue is unique since other new drugs in novel classes, such as fusion and integrase inhibitors can be assumed to be fully active in all patients that have not previously been exposed to drugs in the class.
The concerns regarding the sensitivity of the tropism assay have been markedly reduced with the availability of a modified test with enhanced sensitivity, recognizing that prospective data is not available with this assay. In addition, other assays are being studied which may have some advantages, although thus far have not been as thoroughly validated in clinical trials. Moreover, alternative assays have either been less sensitive for the detection of CXCR4-using virus in vivo or shown to have substantial discordance from the results obtained with the first generation phenotypic assay, and not yet compared to the enhanced sensitivity phenotypic assay that is now routinely used in clinical practice 19, 20.
Where CCR5 antagonist fit into the current treatment paradigm
CCR5 antagonists like others drugs in novel classes have been developed for use in treatment-experienced patients with limited therapeutic options. While these drugs have a role in this setting the fact that they appear to be very well tolerated and that a larger percentage of patients will be found to be candidates for it (i.e. not having detectable CXCR4-tropic virus) earlier in the course of disease argues for the potential use in earlier lines of therapy. In fact, if not used at a time when the patient is shown to not have detectable CXCR4-using virus the drugs may not be an option in the future if these viruses emerge over time. When considering the use of CCR5 antagonists in earlier lines of therapy, including in treatment-naive patient's, clinicians do need to recognize that they have not yet been FDA-approved for this indication and that the phase 3 trial in these patients did not prove non inferiority to efavirenz-containing treatment. However, the reanalysis of that trial using the now routinely available enhanced tropism assay does provide some reassurance. Finally, CCR5 antagonists are new drug in a novel class, a situation where clinicians do need to be alert for potential long-term toxicities.
Cellular target
The fact that CCR5 antagonists target a cellular receptor involved in coordinating immune responses raises unique safety concerns. There is some reassurance knowing that the rare patients born without functional CCR5 genes appear to be relatively healthy. Nevertheless, data suggesting that those born with a mutation in the CCR5 gene may be at some increased risk for severe West Nile Virus infection does emphasize the need for careful observation of patients starting such therapy 5. It is also notable that there were early concerns of increased frequency of malignancies in those treated in a Phase 2b study of the CCR5 antagonist vicriviroc. Nevertheless, further follow-up in this study and the data from the much larger phase 3 studies of maraviroc have not shown such an association. In fact, at this time the data from the larger trials have not raised any specific safety concerns. Regardless, clinicians need to diligently monitor patients treated with any new drugs for unexpected adverse events.
Areas for future research
CCR5 antagonist resistance
A substantial proportion of patients that experience virologic failure while taking a CCR5 antagonist do so with evidence of detectable CXCR4-using virus, even though such strains were not present at the time therapy was initiated 8, 9. This suggests that the emergence of these viruses may represent an important pathway for treatment failure with these drugs. There is also data that some CCR5-using viruses will develop in vitro and in vivo resistance, i.e. the ability to use the CCR5 receptor in the presence of the antagonist 21. Much less is known about how to measure this type of resistance, how frequently it occurs and whether it is associated with cross-resistance between classes. Recent analyses of patients experiencing virologic failure in the phase 3 maraviroc trials used a phenotypic assay and a laboratory cutoff of unknown clinical relevance to address this issue. Jubb and colleagues recently reported that approximately 30% of those experiencing virologic failure with only CCR5-tropic virus had evidence of drug resistance 21. Although further study is needed to determine the clinical relevance of these findings it suggests that if a patient experiences virologic failure and repeat tropism testing demonstrates no detectable CXCR4-using virus there remains a substantial possibility that maraviroc is not contributing to the activity of the drug. In the absence of better data related to maraviroc resistance this would argue that repeated tropism testing at the time of virologic failure on CCR5 antagonists will be of limited value.
Potential role in patients with CXCR4-using virus
CCR5 antagonists are all being developed for the treatment of patients without detectable CXCR4-using virus. These are the patients being studied in the registrational trials and consistent with the lack of antiviral activity seen amongst those with CXCR4-using plasma HIV-1. There remains interest in determining whether a subset of patients with CXCR4-tropic virus may derive benefit from these agents. In fact, studies have attempted to define quantitative or qualitative characteristics of patients with CXCR4-using virus that might derive virologic benefit from a CCR5 antagonist. Swenson and colleagues used "deep" sequencing to demonstrate variable amounts of CXCR4- versus CCR5-using virus in patients treated in the phase 2b study of patients with CXCR4-using virus at screening. This analysis showed a difference in the degree of antiviral activity based upon the quantity of CXCR4-using virus detected by this method 22. Limitations of this study include its small sample size, the use of an assay not clinically available, and the difficulty to adjust the analysis for differences in the background regimen. Nevertheless, it does suggest that this avenue of research could be fruitful in the future and expand the potential role of this novel class of drugs.
Another situation where it is not possible to define the utility of a CCR5 antagonist is in those patients where tropism results are not available. This occasionally occurs for technical reasons, but more often because the assay cannot be performed because plasma HIV-1 RNA is too low or undetectable. In either of these situations there is little data suggesting how to proceed. New assays for plasma virus or for cellular proviral DNA analysis may be of assistance in the future, but for now have not been validated for this indication. While the phase 2b study of patients with detectable CXCR4-using virus included a small number of patients that were "untypable," there were far too few in this group for any assessment of the activity of CCR5 antagonists in this select population. A more common situation where tropism results are not available is in patients experiencing drug toxicity that would like to consider a switch in therapy but have undetectable plasma HIV-1 RNA. Unfortunately, unless a plasma sample is available for testing from prior to the initiation of the current regimen it is impossible to define whether the CCR5 antagonist will be an active drug in this setting.
Prevention of HIV-1 transmission
There has been increasing interest and research into potential biologic means of preventing HIV-1 transmission. This includes pre-exposure prophylaxis with either systemic or local therapeutics. Studies are underway in both arenas with perhaps the most promising results demonstrating that when used topically as a vaginal microbicide, PRO 2000, a synthetic polyanionic polymer that blocks HIV-1 attachment to host cells was able to reduce HIV-1 transmission by approximately 30% 23. There is also interest in testing HIV-1 specific inhibitors as microbicide agents. Since most infections appear to be initiated by CCR5-tropic virus and it is appealing to consider a drug that acts very early in the viral life cycle for prevention of HIV-1 transmission, the potential role of CCR5 antagonists in this setting is being explored.
CCR5 antagonist as immune modulator
The pivotal trials of CCR5 antagonists in patients without detectable CXCR4-using virus have consistently demonstrated better CD4+ T-cell responses amongst those randomized to receive the new drug 8, 9, 11. While this is consistent with the enhanced virologic activity seen in this group, in those treated in the presence of detectable CXCR4-tropic virus there was also a better immunologic response, albeit not significant in those given the CCR5 antagonists compared to controls despite the lack of difference in virologic activity 14. This has led investigators to consider the potential role of these drugs in enhancing immune reconstitution in select HIV-1-infected patients. Thus far these observations remain of interest but are primarily hypothesis generating and have led to other studies to better define these issues. In the interim, there is inadequate data to support the use of this class of drugs for this indication.
Conclusions
The development and approval of a CCR5 antagonist within approximately 10 years of the discovery of CCR5 as a HIV-1 coreceptor is an extraordinary accomplishment. Several well designed clinical trials have demonstrated excellent tolerability along with unequivocal antiviral activity in those without detectable CXCR4-using virus. While this class of drugs brings unique opportunities it also raises novel questions and introduces new complexities for clinicians and patients. At least for now maraviroc has a clear role for treatment-experience patients without detectable CXCR4-using virus by a validated tropism assay. The enhanced sensitivity of the current assay has provided additional reassurance that the drug will be active in this patient population. Further research is underway to define the role of this drug in those starting treatment for the first time, as an immunomodulators and for the potential prevention of HIV-1 transmission.
Competing interests
Eric Daar, M.D. received research support from Abbott Laboratories, GlaxoSmithKline and Merck Laboratories. He is a consultant or advisor for Abbott Laboratories, Bristol Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Laboratories, Pfizer, Schering Plough, Pathway Diagnostics, Tibotec and serves on a Data Safety Monitoring Board for Ardea Biosciences.
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