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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

JOURNAL CLUB - HIV/AIDS

May 2011

Editorial Review

Sharon L. Walmsley, MD, FRCPC, MSc, Director, HIV Clinical Research, University Health Network, Professor of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, Ontario

INTRODUCTION

Judicious use of antiretroviral therapies is essential to preserve limited treatment options and control the threat posed by the exceptional propensity of the HIV virus to mount drug resistance. Canadian consensus guidelines were recently introduced for the optimal use of maraviroc, the only C-C chemokine receptor type 5 (CCR5) inhibitor currently available for the treatment of HIV. Its ability to block the CCR5 receptor, which is employed by HIV to infect cells, has proven to be an effective component of combination therapies for HIV control. The guidelines are designed to provide expert consensus on the appropriate incorporation of this agent into clinical practice. Although the indications from the Canadian Health Protection Branch and the options for tropism testing, which is essential for verifying that patients are candidates for maraviroc, have evolved in the interval between development of the guidelines and their publication, the basic concepts of the guidelines remain valid and provide a basis for the discussion among experts who did and did not participate in guidelines formation.

C-C chemokine receptor type 5 (CCR5) inhibition is 1 of 5 mechanisms of action employed by available antiretroviral agents.¹ With the exception of enfuvirtide, all of the remaining antiretroviral agents suppress HIV infection by inhibiting enzymatic processes within infected host cells.² Enfuvirtide, like CCR5 inhibitors, also prevents retroviruses from entering target cells but it does so by a different mechanism, and it must be administered by injection.³ The drug classes that block enzymatic processes include inhibitors of protease (PIs), reverse transcriptase (nucleoside reverse transcriptase inhibitors [NRTIs] or non-NRTI [NNRTIs]) and integrase (INSTIs).

CCR5 (R5) is 1 of 2 chemokine co-receptors on the surface of the CD4 lymphocyte employed by HIV to attach to the host cell and begin the process of infection, which involves several steps culminating in fusion of the cell and viral membranes.⁴ Viral tropism defines whether a specific HIV strain employs this receptor, its counterpart, the CXCR4 (X4) receptor or both (R5-X4). Early in infection, most viral strains employ the R5 receptor exclusively. With disease progression and drug therapy R5-X4 strains, called mixed tropism, become more common⁵ and usually account for 50% of the isolates. Strains that employ X4 exclusively are rare so non-R5 strains in practical terms may be best characterized as R5-X4 virus.

Unlike inhibitors of viral enzymatic processes within the host cell, receptor inhibitors such as maraviroc and fusion inhibitors such as enfuvirtide preserve the host cell from becoming infected, an approach to HIV control that is conceptually appealing. Several experimental agents employing these mechanisms have been tested clinically but have not advanced for an array of reasons, including adverse events. Vicriviroc, another CCR5 inhibitor, reached phase III clinical testing but is no longer being pursued for clinical use, leaving maraviroc the only CCR5 inhibitor available for routine clinical use.

Clinical Trials

Like many antiretroviral agents, maraviroc was initially tested in treatment-experienced patients. Typical of these trial designs, the participants in the phase III trials, called MOTIVATE-1 (Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment- Experienced Patients-1) and MOTIVATE-2, were randomized to maraviroc (150 mg q.d. or b.i.d.) or placebo in addition to an optimized background therapy.⁶ At 48 weeks, all efficacy end points—including mean viral load reduction and proportion of patients with a viral load <50 copies/mL or <400 copies/mL and an increase in CD4+ cell count—were more than twice as great on either dose of maraviroc relative to placebo. The advantage for reaching undetectable viral loads was highly statistically significant (P<0.001 for all). The activity of maraviroc was further reinforced by the observation that patients treated with this agent were more likely to have sustained viral load reductions even when it was determined that there were no active drugs in the optimized background regimen. Maximal viral suppression was observed when there were more active drugs in the background regimen combined with maraviroc.

As is typical in antiretroviral drug development, the efficacy of maraviroc was then tested in treatment-naive patients. In this study, called MERIT (Maraviroc vs. Efavirenz Regimens as Initial Therapy), patients were randomized to maraviroc (300 mg q.d. or b.i.d.) or efavirenz (600 mg q.d.) in combination with the NRTIs zidovudine (ZDV) and lamivudine (3TC).⁷ In the primary analysis at 48 weeks, maraviroc was noninferior to efavirenz for the proportion of patients with a viral load of <400 copies/mL (70.6% vs. 73.1%) but not for a viral load of <50 copies/mL (65.3% vs. 69.3%) (Figure 1). However, there was early concern that the test used to screen out patients with R5-X4 mixed tropism, called Trofile, was not sufficiently sensitive. This is a fatal flaw for a drug designed for use in R5 virus.

MERIT data were soon reanalyzed using the more sensitive Trofile ES test, which confirmed that approximately 15% of patients in this study had R5-X4 mixed tropism at baseline.⁸ When these patients were excluded, maraviroc, which was better tolerated than efavirenz, was non-inferior for all major end points, including viral load <50 copies/mL (68.3 vs. 68.5) (Figure 1). These results of the reanalyzed MERIT data, known as MERIT ES, were published for both 48 and 96 weeks.^7,8 The 96-week data provided compelling reinforcement of the sustained efficacy of maraviroc by again showing non-inferiority for viral load <50 copies/mL (58.8% vs. 62.7%). For time to loss of virologic response using <50 copies/mL as a threshold of failure, efficacy at 96 weeks was essentially identical (60.5% vs. 60.7%). Results remained similar when evaluating challenging subgroups, such as those with a high baseline load, defined as =10⁵ copies/mL (56% vs. 56.7%).

On the basis of these results, both the U.S. Food and Drug Administration and the Canadian Health Protection Branch (CHPB) amended the initial indication given for treatmentexperienced individuals to include those who are treatment-naive. Although the recently published Canadian guidelines were completed before the MERIT ES data had led to a rewording of CHPB indication for naive patients, guidelines from both the U.S. Department of Health and Human Services and the British Columbia Centre for Excellence in HIV/AIDS have now identified maraviroc as part of an acceptable alternative first-line regimen.

Figure 1.

In both treatment-experienced and -naive patients, the tolerability and safety of maraviroc has been reassuring in the context of available options. The most commonly reported events have been diarrhea, nausea, dizziness, fatigue and headache.^6,7 These occur infrequently and are typically mild. In the MERIT study on treatment-naive patients, maraviroc had a better safety profile than efavirenz with fewer severe adverse events and fewer discontinuations due to adverse events (Figure 2). It also has a benign metabolic profile, with little or no effect on serum lipids or glucose metabolism.

The Canadian Consensus Guidelines

Canadian guidelines provide a comprehensive summary of the experience with maraviroc in treatment-experienced patients but the data from MERIT ES and the progress in tropism testing were released after their completion, thereby limiting some of their current applicability. However, one of the most important assertions, which remains valid, is that maraviroc should be reserved for patients with R5 virus and that tropism testing should be conducted either prior to treatment initiation or soon after. The lesson from the initial MERIT study in the context of MERIT ES was that failure to use tests sensitive for R5-X4 mixed tropism viruses increases the risk for suboptimal viral suppression. In MERIT ES, the reanalysis was performed with Trofile ES, an assay that has demonstrated far greater sensitivity to mixed tropic viruses in controlled studies.⁸ However, several advances in tropism testing have been made since the consensus guidelines were written.

Specifically, while phenotypic tropism assays have been relatively expensive and performed at experienced laboratories, which in some cases required shipping of samples, genotypic population sequencing of the V3 loop can now be performed at lower cost at laboratories already performing resistance testing. In the European consensus guidelines, both the Trofile ES and the genotypic V3 loop sequencing tests have been identified as acceptable, but the consensus panel concluded that genotypic testing is expected to be employed more widely because of its lower cost, its shorter turnaround time and its greater accessibility.⁹ Although not specifically considered in the Canadian guidelines, this is a reasonable approach in this country for the same reasons. It should also facilitate the integration of m
care.

Figure 2.

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Practical Role in HIV Control

Maraviroc may be an appropriate antiretroviral agent in a variety of clinical scenarios, but its unique features suggest an application unlike those of other antiretroviral drugs. While many therapies have been typically considered first-line agents, such as efavirenz or the PI atazanavir, others have been typically reserved for late stages of disease because of their preserved efficacy in patients with multiple resistance mutations, such as enfuvirtide. However, the optimal role of maraviroc for many patients may be as an early secondline agent although it can be considered in the treatment-naive setting. Many patients are well suited to agents identified as preferred in the first-line setting, but maraviroc is an attractive second-line agent when patients fail. In those with R5 virus, the favourable features include a high degree of tolerability, a low risk of adverse effects, including lipid disturbances, and a low risk of producing cross-resistance to other antiretroviral agents.

It is not clear whether tropism testing is useful prior to the start of antiretroviral therapy (ART) in order to monitor the evolution of the infection, but this testing does become attractive as a tool for assessing therapeutic options as patients move to second- or thirdline therapies. One of the advantages of genotypic V3 loop sequencing with the HIV Proviral DNA test is that it can identify R5 virus even when viral loads are undetectable, permitting a switch to maraviroc for reasons other than failure, such as inadequate tolerability. Optimizing the sequence of ARTs is essential because therapeutic options narrow over time due to emergence of mutations and cross-resistance. It is important to understand the unique features of maraviroc and where it fits along the trajectory of
e this agent successfully into daily practice (Table 1).

Table 1. <img4820|center>

Summary

The Canadian consensus guidelines for the role of maraviroc are useful for outlining the clinical features of this agent, but new data released subsequent to the guideline deliberations limit some of the conclusions. In particular, the data demonstrating long-term efficacy in treatment-naive patients and the introduction of the genotypic V3 loop sequencing test are reorienting the clinical application. While some guidelines now list maraviroc as an alternative first-line antiretroviral drug, genotypic testing facilitates its use in early second-line treatment, particularly for those considering a switch despite an undetectable viral load. The ability of genotypic testing to identify R5 virus in such patients means that it can be reliably considered in the setting where it is most useful, which is prior to late-stage viral evolution when mixed tropism becomes more likely. As a well-tolerated agent with a unique mechanism of action, maraviroc has specific qualities to consider for its application in clinical care.

References

1. Hughes et al. New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir. Expert Opin Pharmacother 2009;10(15):2445-66.

2. Warnke et al. Antiretroviral drugs. J Clin Pharmacol 2007;47(12):1570-9.

3. Hughes A, Nelson M. HIV entry: new insights and implications for patient management. Curr Opin Infect Dis 2009;22(1):35-42.

4. Shaheen F, Collman RG. Co-receptor antagonists as HIV-1 entry inhibitors. Curr Opin Infect Dis 2004;17(1):7-16.

5. Weinberger et al. Accelerated immunodeficiency by anti-CCR5 treatment in HIV infection. PLoS Comput Biol 2009;5(8):e1000467.

6. Gulick et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008;359(14):1429-41.

7. Sierra-Madero et al. Efficacy and safety of maraviroc versus efavirenz, both with zidovudine/lamivudine: 96-week results from the MERIT study. HIV Clin Trials 2010;11(3):125-32.

8. Cooper et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis 2010;201(6):803-13.

9. Wensing AMJ. Consensus statement of the European guidelines on clinical management of HIV-1 tropism testing. JAIDS 2010;13(suppl 4):Abstract 0121.

questions and answers

Panel

Jean-Pierre Routy, MD, Division of Hematology and Immunodeficiency Service, MUHC-Royal Victoria Hospital, Associate Professor, Division of Experimental Medicine, McGill University, Montreal, Quebec

Joss J. de Wet, MBChB, CCFP, Spectrum Health, Clinical Assistant Professor, Department of Family and Community Medicine, University of British Columbia, Vancouver, British Columbia

Colin M. Kovacs, MD, FRCPC, Maple Leaf Medical Clinic, Associate Professor of Medicine, University of Toronto, Toronto, Ontario

What are the key strengths of an antiretroviral agent that inhibits CCR5?

Dr. Routy: An oral antiretroviral agent that blocks the virus from attaching to the target cell receptor rather than preventing intracellular viral replication is unique in the HIV drug armamentarium. Although the concept of blocking viral entry was pioneered with T-20 [enfuvirtide], that drug had to be administered by subcutaneous injection. Viral control is dependent on employing several drugs with different mechanisms of action because of the high risk of resistance mutations, so unique mechanisms of action are attractive.

Dr. de Wet: The most important key strength is the novel mechanism of action. It inhibits the binding of the virus to the CCR5 receptor that is needed for cell entry. This receptor is utilized by a large proportion of viruses. It is a first in class and we have not yet had any failures due to resistance with this agent in the community. It is also important to emphasize that this drug is very well tolerated. For the appropriate candidates, it has a very low risk of side effects, and it does not appear to have any adverse metabolic effects or impose other problems with the potential for longterm complications. The exception may be the elevations in liver enzymes, but clinically significant elevations have been relatively uncommon, occurring in less than 5% of patients in controlled clinical trials.

Dr. Kovacs: For comparing mechanisms of action, there is no evidence yet to say that CCR5 inhibition confers any special advantages in viral load decay characteristics over the actions by which standard antiretroviral therapies suppress the viral load. However, maraviroc has demonstrated a virologic potency that appears to be on the same level of some of the other antiretroviral options, and it does appear to have a very good safety profile, which may derive from its extracellular activity. Nevertheless, it is worth noting that it is always useful to have more mechanisms of action within any given armamentarium of drug options to treat HIV infections in order to combat the development of drug resistance and to provide patients with options to combat tolerability issues.

Dr. Walmsley: The CCR5 inhibitors were developed based upon the observation that individuals who have the delta 32 receptor mutation in the chemokine receptor CCR5 have a decreased risk of acquiring HIV infection and should they be infected, they would have a slower progression of disease. It then seemed logical that blocking this receptor might be a useful therapeutic agent. When an individual is initially infected with HIV, the virus typically uses the CCR5 as its co-receptor to enter the cell. Blocking this receptor would then be an effective form of antiretroviral therapy. The key strengths of using drugs that block the R5 receptor is that this is a newer class of drugs and therefore most individuals will be infected with viruses that are susceptible to this agent. Secondly, these are agents that act externally from the cell and therefore theoretically will be associated with lesser toxicity. Thirdly, because of this unique mechanism of action, it is not anticipated that there will be much in the way of drug interactions of therapies that patients are using either to inhibit their HIV or for the management of comorbidities.

What tolerability or safety issues, including risks of metabolic disturbances, are important for clinicians to consider with CCR5 inhibitors?

Dr. Walmsley: Because the CCR5 inhibitors represent a class of drugs that act upon a cellular receptor rather than the viral receptor, there were obviously some concerns that this could be associated with some unknown toxicity. However, this has not occurred in the studies that have been reported to date. Longterm follow-up of individuals that have been involved in the clinical trials of maraviroc have not shown an excess of malignancy relative to the control group and if anything, the incidence of malignancies is decreased; this is likely related to the improved immune restoration in the group who have received maraviroc. In addition, because some viruses such as West Nile might use this receptor, there was some concern that viral infections would be increased in this group but again, in the clinical trials that have been reported to date, this has not proven to be the case. In the initial dose-finding studies of this compound, hypotension was associated with larger doses; this has not been associated with the doses in clinical trials. Therefore, for the most part, this appears to be a safe and effective agent. It has a better tolerability profile than some of the other antiretrovirals currently in use and there were no adverse events in the clinical trials that were reported more frequently with this drug than in the placebo arm.

Dr. de Wet: As I have already stated, the tolerability and low risk of adverse events is one of the strengths of maraviroc, but there is a black box warning regarding the risk of hepatotoxicity. The reason for this warning may owe more to the withdrawal of an earlier CCR5 inhibitor, aplaviroc, which was withdrawn from clinical testing due to hepatotoxicity, than from maraviroc. In the MOTIVATE trials with maraviroc, liver enzyme elevations, which were monitored closely because of the experience with aplaviroc, led to study discontinuation in only 1.4% of patients. However, I would be reluctant to use maraviroc in a patient with hepatitis.

Dr. Routy: The low rates of clinical and laboratory side effects have been reassuring. One of the advantages of the R5 inhibitors is that their activity is on the cell surface, so there is a reduced risk of dysfunction of cellular activities, including changes in mitochondrial function. As patients are on these therapies for extended periods, any side effect can be difficult to tolerate. When we mainly had PIs, which were essentially saving the lives of patients with HIV, there was still major dissatisfaction with lipodystrophies. Avoiding significant side effects is very important to most patients, even if these adverse effects are not life-threatening.

Dr. Kovacs: Maraviroc has proven safe and well tolerated in clinical trials. The absence of any important changes in lipid or glucose metabolism is an attractive feature. There appears to be no association with mitochondrial dysfunction and there are no data suggesting that there will be any renal issues of significance. The development of agents without significant adverse effects is especially welcome and reassuring in the context of the growing concern about the cumulative metabolic problems in aging HIV-positive patients facing diabetes, cardiovascular disease, bone disease and other issues. Given that antiretroviral therapy is lifelong without interruption and now, with the appropriate antiretroviral initiation guidelines recommending earlier times to start therapy, one can envision that patients will be on antiretroviral therapy for decades. Starting with or changing to antiretroviral agents that are tolerable, both from a side effect and a toxicity profile, has now become the most important challenge in the long-term treatment of HIV patients.

Traditionally, newly introduced agents have been limited to the salvage setting. CCR5 inhibitors may not be optimally used for salvage. Do you think this will confuse clinicians about proper application?

Dr. de Wet: Maraviroc is not appropriate in highly treatment-experienced patients because of the greater likelihood of X4 virus. A CXCR4 virus would obviously not respond to maraviroc which inhibits only the co-receptor CCR5, thus we cannot use this agent in the salvage setting. It has to be used in earlier lines of treatment, either first or second, before the virus switches tropism. The best role for this agent is front-line or early second-line.

Dr. Kovacs: In an ideal situation in which there is full access to treatment options, then maraviroc should be used relatively early in the sequence of agents. Certainly, it is not ideal in late stages of infection, when mixed tropic viruses are more common and when it is combined with other agents that are less than fully active. The axiom of HIV therapy is to use 3 fully active agents (ongoing research is examining other strategies). However, currently in Canada, we have regions of the country wherein the access to maraviroc is being severely limited to a small number of patients who demonstrate late end-stage failure with documented triple class resistance on genotype. As well, there has been no allowance by the funders for the usage of this drug in suppressed patients experiencing serious side effects or toxicities. This is less than optimal for the utilization of this drug. This restricted use of the drug solely for end-stage salvage therapy endangers the long-term health and wellbeing of the HIV community at large. The current criteria that the funders have utilized are based on a single trial in triple-class, heavily experienced patients with limited options. This is simply a potency trial; the results should never be extrapolated such that the criteria for funding nullify the plethora of evidenced-based trials documenting that the basic axiom of HIV therapy be the incorporation of 3 fully active medications to achieve long-term, durable virologic suppression of HIV in plasma.

Dr. Walmsley: Maraviroc or CCR5 inhibitors have a role in the entire spectrum of HIV disease provided that the individual virus is R5-tropic. The drug was first evaluated in people who had treatment experience because of the fact that this was an unmet need and there was a more urgent need for development of new agents. Clearly, in patients in this salvage situation who continue to have R5-tropic virus, this is an important drug to be added to their combination therapy. In the clinical trials, patients who had maraviroc added to their background therapy were more than twice as likely to suppress viral replication than those who did not receive the drug. Clearly, however, the drugs are also effective at earlier stages in disease, provided that the individual has R5-tropic virus. Therefore the drug does have a role in all stages of disease provided that the patient has R5 tropic virus and it is paired with other active agents.

Dr. Routy: Many of the newer agents which are effective against resistant virus, such as darunavir, are being considered for initial therapy or relatively early in the disease. There does appear to be a reorientation in regard to first-, second- and third-line agents. Due to the natural history of viral infections, CCR5 inhibitors should be used early in the disease in order to limit the ability of the virus to switch to the X4 receptor for infection. With tropism testing, it is possible to identify patients in whom a CCR5 inhibitor will still be effective even late in disease, but the general approach is to introduce this mechanism of action relatively early rather than reserve the agent for those who have failed multiple classes.

Are there situations in which you might use a CCR5 inhibitor within a first-line combination?

Dr. Walmsley: The CCR5 inhibitors have now been approved by the FDA and in Canada for first-line use in patients with R5-tropic virus. In the clinical trials it has been found to be non-inferior to efavirenz as part of firstline therapy. Obviously, whenever choosing a drug for patients to initiate antiretroviral therapy, there has to be a balance between efficacy and toxicity. As the CCR5 inhibitors are more costly and do require the additional step of tropism testing, they may not always be a cost-effective first-line choice. However, given the better tolerability, the lack of drug interactions and the improved lipid profile, there certainly are individuals for whom maraviroc would be a most appropriate firstline therapy.

Dr. Routy: There are many effective and welltolerated options for first-line therapy, so I would not routinely consider maraviroc in this setting. We have years of experience with some of the preferred regimens, so I do not see an advantage to switching to a newer agent. However, there are some relatively rare situations in which maraviroc can be considered, particularly those patients infected with a multiresistant strain. In primary resistance, these viruses may still be R5-susceptible, so maraviroc would be an attractive choice.

Dr. de Wet: Maraviroc has been listed in the most recent DHHS guidelines as an acceptable alternative for first-line therapy. It is an alternative to the preferred efavirenzcontaining regimen. Maraviroc was compared to efavirenz in the first-line setting, when the dataset was re-analyzed with the new more sensitive tropism test, it demonstrated non-inferiority to efavirenz with fewer discontinuations due to side effects but more discontinuations due to virologic failures. It is therefore an alternative regimen and can definitively be used in patients who cannot tolerate efavirenz or any other first-line regimen that cannot be tolerated due to side effects.

Dr. Kovacs: There is no reason why this drug might not be used front-line, particularly if we gain data that confirm once-daily dosing is effective. At this point, there are no characteristic mutations associated with maraviroc therapy that would be expected to confer resistance to other antiretroviral agents. We have more experience with the guidelinerecommended preferred regimens for naïve patients, but the guidelines will evolve as the therapeutic options evolve, and there is no inherent reason not to consider maraviroc as a first-line therapy.

How accurate and reliable is current tropism testing? In the registration trials, specificity for CCR5-only virus seemed to be a problem; is this still the case? Will newer tests, such as proviral DNA testing, be important to establish CCR5 status even in non-detectable patients?

Dr. Kovacs: There is a lot of interest in the relative merits of the proviral DNA test (cellbased) relative to the enhanced Trofile test or the g2p testing, both of which rely on plasma HIV RNA, but the comparative data are very limited so far. Several institutions overseas have now commenced incorporating the cell-based technology as part of their routine testing of tropism in patients who are suppressed and in whom there are no frozen samples to measure plasma tropism. Recent reports have shown that the proviral DNA test is a good clinical predictor of virologic success when compared to the plasma RNA tropism testing in some clinical situations. The proviral DNA test may have several advantages, including the ability to identify viral tropism in patients with undetectable viremia, and the preliminary data are very promising, but to date this technology has not been incorporated into everyday clinical practice. In my experience, the proviral DNA test has been selectively helpful in managing suppressed patients with significant toxicity issues. The prospective clinical trials designed to evaluate the clinical predictability of relying on proviral DNA measurements are underway.

Dr. de Wet: The newer ultrasensitive test and the genotyping test both appear to be reliable. The development of more sensitive tests was essential because tropism testing has been the Achilles’ heel for the CCR5 inhibitors. The inadequate sensitivity of the Trofile test used in the MERIT study now appears to explain why the study was unable to show non-inferiority for maraviroc relative to efavirenz. Now, with genotyping, we appear to be getting reliable results relatively quickly, so this can facilitate the use of an R5 inhibitor.

Dr. Routy: The ultrasensitive and genotype tests have demonstrated good reliability. The advantage of the genotype test is that you do not have to grow virus, so it is rapid. The accuracy of these tests facilitates patient selection and provides reassurance that patients will respond.

Dr. Walmsley: Tropism testing has evolved over the years. The Trofile tests that were used in the original studies were not that sensitive and could not detect mixed-tropic virus if they represented up to 25% of the population. With the new improved Trofile test (ES), we were then able to pick up mixed-tropic virus that was represented by as little as 1% of the population. The problem with the Trofile testing, however, is that it does require the testing of live virus and this added an additional step and cost. More recently, there have been genotype tests that have been developed which, during evaluation, have been shown to be as predictive as the ES in determining the individuals who would respond appropriately to the CCR5 inhibitors. The advantage of the genotype tests is that they can be done in multiple labs throughout the world, they can be done in patients who have a suppressed viral load (and therefore can be also useful in the evaluation of patients for switch therapy) and have a more rapid turnaround time with less expense.

The CCR5 studies appear to link these agents with good immunologic recovery in regard to CD4 counts. Do you think this is a function of their ability to prevent virus from entering T-cells?

Dr. Walmsley: In the clinical trials, it has been demonstrated that patients who have received maraviroc have an improved CD4 count response relative to individuals who do not receive maraviroc. The significance of this improved CD4 count however has not yet been determined and no clinical end point trials have been carried out. It is unclear whether or not this improved CD4 count will result in decreased opportunistic infections or malignancies. Some of the earlier studies have also shown that this improved CD4 count response is associated with decreased immune activation which again could theoretically be useful for a person with HIV. To date, the studies giving maraviroc in addition to other compounds to patients with suppressed viral load but who have had an inadequate CD4 count response have been disappointing, but these studies so far are small and the questions remain.

Dr. de Wet: Several studies comparing newer agents to established agents have associated the newer ones with a faster increase in CD4 cells, but the suggestion that this demonstrates a clinically meaningful difference in immunologic recovery is uncertain.

Dr. Kovacs: The difference in the rates of CD4 recovery on various antiretroviral combinations has been very difficult to interpret. One problem is that there are some differences in the methodology with which CD4 cells are measured, but findings from different studies have also been inconsistent. None of the trials have reported other features of immune repair, i.e. CD4 percentage, absolute CD8, activation markers and ratio values. Although faster immunologic recovery has some theoretical advantages, there are no data supporting differences in clinical outcomes. The absolute rise in CD4 count may only be a very rough indicator of immunologic recovery, and so far it has been difficult to tease through the data when comparing different therapies.

Dr. Routy: I am not sure what the significance of the faster immunologic recovery with maraviroc in comparative trials means. We do not see any clinical differences in regard to immune function when maraviroc is combined with the most commonly used antiretrovirals. It is possible that there may be some value in patients with a low CD4 count when added to another agent associated with rapid immunologic recovery, such as raltegravir, but evidence is needed to show clinical differences. We are now studying this approach.

Although strategies for optimal use of antiretroviral therapies appear to be in constant evolution, do you feel comfortable with current applications of CCR5 inhibitors?

Dr. Routy: There are a number of potential basic science and clinical studies that could expand our understanding of the optimal application of maraviroc. In particular, I think it would be appropriate to gather more details about the role of maraviroc as an immune modulator agent. Specifically, there should be more studies of how this agent boosts immunologic recovery and whether it has a meaningful impact on immune function.

Dr. Kovacs: I think it is likely that we will see an expanding list of clinical applications with more experience. Independent of its mechanism, maraviroc has demonstrated good efficacy and safety within an antiretroviral combination, but it will make sense to consider an oral entry inhibitor in strategies for prophylaxis, such as vaginal gels or postexposure regimens. It is typical to adjust the application of drug therapies as new information becomes available, and this will be no different with maraviroc, but I think this agent has a particular potential for expanded indications in the control of HIV.

Dr. de Wet: In my opinion, more research needs to be done to identify the appropriate applications of this CCR5 inhibitor. It has only been studied with the old backbone of zidovudine and lamivudine, and there is therefore a paucity of data. I can see a definite utility in the first and earlier lines of treatment, specifically in the patient who cannot tolerate available antiretroviral agents. Maraviroc has very few side effects and is well tolerated, but we need more data for its specific applications.

Dr. Walmsley: Antiretroviral therapy strategies continue to change and I think that the CCR5 inhibitors are very useful for patients at multiple stages of disease, provided that they have R5-topic virus. These agents provide us with a new class of drug to which the patient’s virus could be anticipated to be susceptible.