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PRIORITY PRESS - XVIII International AIDS Conference (IAS)

Vienna, Austria / July 18-23, 2010

In patients with a failing immune system due to HIV infection, combination antiretroviral therapy (ART) must be maintained more or less continuously to control disease. The combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-NRTI has been widely recommended and employed as the first-line regimen due to high levels of efficacy and safety, but second-line and subsequent regimens required by either intolerance or resistance must be selected prudently to preserve treatment options. Traditionally, the newest drug classes, which typically retain efficacy in patients with multiple resistance mutations, have been reserved for the most advanced disease. This approach is evolving.

Resistance Profile and Efficacy

According to Dr. Jürgen Rockstroh, Head, HIV Outpatient Clinic, University of Bonn, Germany, “We have a great deal more latitude to individualize therapy with the current options. There are situations in which it makes sense to use one of the newer agents early. When cross-resistance is not an issue, the order of treatments can be based on other considerations.” The clinical application of CCR5 inhibitors provides a clear example of this change in orientation. Although the currently available CCR5 inhibitor, maraviroc (MVC), has a unique resistance profile, it appears to be more appropriate in first- or second-line therapy than in salvage therapy because of evolving viral characteristics in advanced disease that reduces the proportion of patients likely to respond relative to earlier stages of HIV infection.

In a series of case studies presented during a symposium devoted to when and how to evaluate whether HIV patients are candidates for entry inhibitors, MVC was repeatedly identified as an attractive substitute for patients with intolerance to the non-NRTI efavirenz or any of the ritonavir-boosted protease inhibitor (PI/r) therapies, such as atazanavir (ATV) or lopinavir. Like other newer agents, it was initially tested and demonstrated efficacy in the salvage setting if combined with at least one other active agent. A subsequent set of studies in treatment-naive patients also demonstrated a high degree of efficacy as well as an unusually favourable safety profile. In the key trial, called MERIT-ES, the CCR5 inhibitor was as effective as efavirenz when patients were screened for CCR5-using virus and both were combined with two NRTIs.

In the MERIT-ES study—which led the U.S. Food and Drug Administration (FDA) to approve the novel agent for first-line therapy—the proportion of patients with undetectable viral load (<50 HIV RNA copies/mL) at the end of 96 weeks was approximately 60% in both arms. In addition, the time to loss of virologic response and the proportion of patients who remained on therapy were also statistically indistinguishable.

CCR5 Tropism

An earlier MERIT analysis did not find the CCR5 inhibitor to be non-inferior to efavirenz, but this was proven to be due to the insensitivity of the test for CCR5 tropism. It is the importance of CCR5-tropic virus that makes the novel agent a more appropriate choice for first- or second-line therapy than salvage.

As explained by Dr. Daniel Kuritzkes, Director of AIDS Research, Brigham and Women's Hospital, Harvard Medical School, Boston, “Maraviroc controls HIV by preventing the interaction between HIV and the chemokine receptor CCR5 on the host cell. For the CCR5-using virus, this is a highly effective mechanism of action.” He indicated that recognizing the importance of CCR5 tropism is critical to understanding the role of this drug class. In treatment-naive patients, an estimated 80% of infections use the CCR5 receptor exclusively to gain entry to the lymphocyte. The only other receptor, CXCR4, is also used or used alone by the remainder of infections. In patients with advanced disease, the proportion of infections using the CCR5 receptor is smaller, so that 50% to 70% are highly susceptible to a CCR5 inhibitor with far less efficacy anticipated in mixed tropic or CXCR4-using infections, which represent the remainder.

First- and Second-line Strategy

Dr. Annemarie Wensing, Senior Consultant in Clinical Virology, University Medical Center, Utrecht, The Netherlands, suggested, “MVC is not a drug that is best reserved for deep salvage.” Although CCR5 inhibitors have been shown to be highly effective in advanced infection using the CCR5 receptor for entry, Dr. Wensing reported that tropism testing is now routine even in early disease at her institution. She indicated that this testing provides a fuller awareness of options and allows planning if the next option fails due to intolerance or lack of efficacy.

As a factor for early use of MVC, tolerability is one of the most significant advantages, according to Dr. Rockstroh. This agent does not share any of the neurological toxicities common to efavirenz and it is metabolically neutral, distinguishing it from several PI/r agents. In the placebo-controlled MOTIVATE trials, it demonstrated no clinically significant differences in safety signals vs. placebo. This not only makes it a reasonable second-line therapy for those who have poorly tolerated the initial regimen, but it has also led to studies evaluating it in novel regimens specifically designed to reduce risk of complications.

The most significant of recent trials, presented as a late breaker at the IAS meeting, was a pilot study evaluating MVC in a two-drug nucleoside-sparing ART. This was one of several recent efforts to avoid the potential side effects of NRTIs, such as reported in a recently published experience with MVC, raltegravir and etravirine (Nozza et al. AIDS 2010;24:924-8), and the results were promising.

Study A4001078 Findings

“The rationale for doing this study is to identify a once-daily, low-pill-burden regimen that is nucleoside toxicity-sparing,” stated Dr. Simon Portsmouth, Consultant and Lead Clinician in HIV Medicine, St Mary’s Hospital, London, UK. He noted that the attributes of MVC include good penetration of the cerebrospinal fluid (CSF) and genital compartments and its low susceptibility to generating resistance mutations to other ARTs in the event of failure.

In the open-label, phase IIb A4001078 study, 121 treatment-naive patients were randomized to MVC 150 mg q.d. or a standard regimen of tenofovir 300 mg and emtricitabine 200 mg both administered with a standard dose of ATV/r. The primary outcome was proportion of patients with undetectable HIV (<50 copies/mL). Presenting the 24-week interim analysis, Dr. Portsmouth reported that baseline characteristics were similar in the two groups.

At 24 weeks, the proportion of patients with undetectable levels was 80% or greater in both arms and statistically indistinguishable. Typical of past studies, the median increase in CD4+ cell counts was much greater on the CCR5 than on the comparator therapy (190 vs.159 cells/mm3). Although the rate of grade 3 or 4 adverse events was higher in the arm that included MVC (33.3% vs. 21.3%), the rate of discontinuations for adverse events was only slightly greater (3% vs. 0%).

Although MVC is typically dosed twice daily, the once-daily regimen in this study was supported by evidence that PI therapy increases the CCR5 inhibitor concentrations. In presenting pharmacokinetics substudy data, Dr. Portsmouth reported that MVC concentrations remained several-fold above the target throughout the study. There was no change in phenotypic tropism observed, suggesting in this study, as in past trials, that MVC does not produce selective pressure to move to a CXCR4-tropic virus. On the basis of these interim results and the importance of developing NRTI-sparing regimens, “a phase III study is now planned,” Dr. Portsmouth told delegates.

The greater likelihood of an optimal response in early treatment with MVC suggests that this therapy should be used earlier rather than later in the course of HIV infection. However, other newer agents may also be moved forward in the shifting understanding of how to maximize and preserve options while providing patients with well-tolerated therapies. For example, raltegravir, the integrase inhibitor, is also metabolically neutral in regard to lipids and may make more sense at a relatively early stage of disease than some PI/r therapies in patients who already have an elevated cardiovascular risk. These types of shifts in ART application are now being explored in clinical trials.

Summary

The clinical experience with a CCR5 inhibitor has provided an example of how the introduction of newer ARTs is changing the traditional sequence of treatments in patients with advancing HIV. Agents with novel mechanisms of action were generally reserved for the salvage setting, yet this does not appear to be the case with MVC and may not be appropriate with newer agents in specific clinical applications. Further evolution in how ARTs are used in relationship to each other appears likely.