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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.

PHYSICIAN PERSPECTIVE Viewpoint based on presentations from the HIV DART 2008 - Frontiers in Drug Development for Antiretroviral Therapies

Rio Grande, Puerto Rico / December 9-12, 2008

Reviewed by:

P. Richard Harrigan, PhD

Director, Research Laboratories, British Columbia Centre, for Excellence in HIV/AIDS

Associate Professor, Division of AIDS, University of British Columbia, Vancouver, British Columbia

Like most new antiretroviral (ART) agents, the first CCR5 antagonist, maraviroc, was granted accelerated regulatory approval based on clinical trials in the salvage HIV setting. The two multinational clinical trials that evaluated maraviroc followed a pattern established with other novel agents, such as the injectable entry inhibitor enfuvirtide (T-20). When compared to placebo in patients receiving an optimized background regimen (OBT) of ART therapies, the likelihood of achieving undetectable viremia, whether defined as <400 HIV RNA copies/mL or <50 copies/mL, was more than doubled with the addition of maraviroc. In studies now completed in treatment-naïve patients, maraviroc has also been found to be well tolerated, compatible with other ART agents, and effective in once-daily dosing.

Until recently, there was widespread concern that a large proportion of HIV-infected patients would soon begin to cycle through treatments faster than drug development was able to provide new compounds. For the most part, this has not occurred. A number of new drugs have been introduced over the past several years that have demonstrated efficacy in the salvage setting, often providing undetectable levels of viremia when patients were switched at a time when they had at least one other therapy to which their retrovirus was susceptible. Entirely new classes of ART agents would be expected to provide the best defence against existing resistant variants but drugs with completely new mechanisms of action are rare.

Maraviroc is the first agent from a new class of ART drugs called CCR5 antagonists. These agents bind to “CCR5,” one of the two human proteins used by HIV as co-receptors to enter CD4+cells. Binding of the drug to this protein can block the entry of CCR5-using HIV into these cells. These compounds do not inhibit HIV, which uses the other co-receptor (CXCR4); therefore, individuals must be screened for co-receptor usage (or “tropism”) to ensure their virus uses CCR5.

MOTIVATE 1 and 2 TRIALS

The activity of maraviroc in the initial salvage studies, called MOTIVATE (Maraviroc vs. Optimized Therapy In Viremic Antiretroviral Treatment-Experienced patients) confirmed the sustained viral suppression demonstrated in pilot studies. In both MOTIVATE 1, which was conducted in Canada and the US, and MOTIVATE 2, which was conducted in the US, Europe, and Australia, patients were randomized to maraviroc 150 mg q.d., maraviroc 150 mg b.i.d., or placebo plus OBT.1 The large reductions in viral load achieved were sustained over follow-up that is approaching two years with no signature side effects yet emerging.

At 48 weeks, the proportion of patients with a viral load <50 copies/mL, a critical goal for sustained HIV suppression, was 45% in both active treatment groups vs. 18% in the placebo group in one of the MOTIVATE studies, and 42% and 47% in the q.d. and b.i.d. groups, respectively, vs. 16% for placebo in the other study (P<0.001 for either dose in both studies vs. placebo). The CD4+ cell count increases ranged from 113 to 128 cells/mm³ for those randomized to maraviroc vs. 54 to 69 cells/mm³ for placebo (P<0.001 for maraviroc vs. placebo in either study). Now at 96 weeks, there has been very little attrition. In the placebo group, only 7.2% of patients remain <50 copies/mL vs. 38.9% for those receiving maraviroc q.d. and 41.3% for those receiving it b.i.d. (P<0.001 for either regimen of maraviroc vs. placebo) (Figure 1).

Figure 1.

These relative rates of viral control and immune reconstitution are greater than those reported in previous salvage studies, which may be at least in part due to changes in the way salvage studies are now conducted. Unlike many earlier salvage studies, such as the TORO (T-20 vs. Optimized Regimen Only) study with enfuvirtide2 or the RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir) studies,3 the MOTIVATE trials were more likely to recruit patients before they had exhausted all other ART options. Based on the important lesson from the early salvage trials that response rates are much greater in those who have at least one additional active drug, it has become important to introduce new agents before the patient has exhausted other options.

This strategy is far easier to pursue with the increasing number of agents effective against resistant HIV, particularly the development of agents such as maraviroc which are well tolerated and permit convenient administration. As the first entry inhibitor, enfuvirtide is highly effective in preventing HIV entry by inhibiting attachment of the viral envelope to the surface of the target cell, but the requirement for daily injections and the nearly universal occurrence of mild to moderate injection-site reactions rendered this agent relatively unpopular. Several new members of the protease inhibitor (PI) class of ARTs are highly effective for resistant HIV infection but may be burdened by other issues, such as disturbances in lipid metabolism or cumbersome dosing.

Maraviroc appears to be well-tolerated. Specifically, no clinically relevant differences in safety were identified in the MOTIVATE studies when the maraviroc and placebo arms were compared. Although the total rate of adverse events was slightly lower on placebo (85% vs. 91%/92%; P=0.01), there was a higher rate of discontinuation on placebo. A comparison of specific side effects did not reveal obvious concerns. For example, the difference in the rates of fever reached statistical significance, but these were 2% in the once-daily maraviroc group, 4% in the placebo group, and 6% in the twice-daily maraviroc group. Headache occurred in 6% of placebo patients, 5% of once-daily maraviroc patients, and 2% of twice-daily maraviroc patients (P=0.03 for the twice-daily dose). No side effect was observed in more than 6% of maraviroc patients except diarrhea, which was reported by 10% of those on once-daily maraviroc, 8% of those on twice-daily maraviroc, and 10% of those on placebo.

The acute tolerability of maraviroc will be an even more important asset if the current evidence of sustained safety is confirmed. While the adverse effects of many first- and second-generation PIs on lipids were not fully appreciated for several years, producing caution about premature conclusions about safety, maraviroc does not significantly influence lipid or glucose metabolism, liver or renal function, or other systemic activities that raise concern about the potential for a cumulative risk. There is also no evidence that this agent significantly alters the activities of other ART agents, which is another important attribute for an agent included in sustained combination regimens.

MERIT Studies and CCR5 Tropism

Although many novel therapies have remained largely confined to salvage applications, the attributes of maraviroc make it potentially attractive in the first-line setting. In a multinational trial called MERIT (Maraviroc vs. Efavirenz Regimens as Initial Therapy), 721 treatment-naïve patients were randomized to maraviroc 300 mg b.i.d. or efavirenz 600 mg q.d. Both agents were administered in combination with a co-formulation of zidovudine and lamivudine. As in the MOTIVATE trials, all candidates were screened prior to entry for CCR5-tropic virus and excluded for CXR4-tropic or mixed-tropic HIV strains using the original TrofileTM test performed by Monogram Biosciences.

When initial results of MERIT were presented at the 4th International AIDS Society Conference on HIV Treatment in Sydney, Australia,4 maraviroc was found to be slightly less effective in achieving HIV levels <50 copies/mL (65.3% vs. 69.3%), particularly among those with baseline viral loads >100,000 copies/mL (60.0% vs. 66.0%). However, the difference between maraviroc and efavirenz for the outcome of <50 copies/mL was confined to countries of the southern hemisphere (62.1% vs. 71.0%) and not observed in countries of the northern hemisphere (68.0% vs. 67.8%). Regardless of geography, maraviroc was associated with a higher median CD4+ cell count increase (170 cells/mm³ vs. 144 cells/mm³ for efavirenz).

New data have suggested that the small difference in virological suppression between maraviroc and efavirenz may have resulted from the screening assay that was used in the trials, the original Trofile assay. This test was used to exclude patients whose virus used the CXCR4 co-receptor (rather than CCR5) from entering the study of this CCR5 antagonist. A modified version of this test has now shown that the original Trofile test was not sufficiently sensitive at detecting CXCR4-using virus.

In a subsequent analysis of the MERIT data, called MERIT ES, the slight disadvantage for viral control associated with maraviroc was eliminated among those whose CCR5 tropism was confirmed with the new, more sensitive assay that increased sensitivity for CXCR4 variants by 30-fold.5 When patients with CXCR4 virus were eliminated in this post-hoc analysis, the proportion of patients achieving a viral load <50 copies/mL was exactly the same (68%) for both compounds. In those with a baseline viral load >100,000 copies/mL, the proportion achieving a viral load <50 copies/mL was 64% and 63%, respectively, for maraviroc and efavirenz. The proportion <400 copies/mL was 73% and
ure 2).

Figure 2.

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The fact that maraviroc is not effective in patients with a virus that employs the CXCR4 co-receptor for entry was known and expected. However, this group represents a relatively small percentage of patients in North America, where it is estimated that 80% or more of HIV infections are CCR5-only viruses. While the greater sensitivity of the improved assay is welcome, new methods of testing for CXCR4-using virus are in development. Genotyping, which looks for viral genetic signatures of co-receptor use, may prove to be faster and less expensive than phenotyping while retaining or improving the sensitivity and specificity of the best phenotypic tests. It is likely that alternatives to the current screening test will become more widely available in the near future.

Maraviroc is the first in its class, but it is not the only CCR5 entry inhibitor to demonstrate efficacy in a clinical setting. Although initial clinical studies with the CCR5 inhibitor vicriviroc generated concerns about possible links to malignancy, these have not been supported in subsequent clinical trials, and a phase III registration study is now fully enrolled. In the phase II VICTOR-E1 (Vicriviroc In Combination Treatment with Optimized antiretroviral therapy Regimen in Experienced subjects), vicriviroc was associated with a significant advantage over placebo for the end point of viral load <50 copies/mL (56% vs. 16%) at 48 weeks. Like maraviroc, vicriviroc also produced a higher-than-anticipated CD4+ cell increase.6 The potential clinical importance of the greater-than-predicted rise in CD4+ cell counts with both CCR5 inhibitors is being followed closely.

Screening a Prerequisite

Screening for CCR5 tropism is a prerequisite for use of CCR5 inhibitors, but the value of genotyping in current HIV drug resistance testing suggests that such tests may eventually be a routine step in patient evaluation. Eventually, the goal of genotyping may extend substantially beyond the detection of baseline resistance mutations or entry-receptor tropism. Rather, creating a full genomic sequence of each HIV infection at baseline may eventually prove useful in documenting evolution in the virus and guiding therapeutic choices along the course of disease.

Currently, CCR5 inhibitors have potential utility both early and late in HIV infection depending on a variety of clinical factors. Although a higher percentage of patients appear to develop CXCR4 viruses at late rather than early stages of disease, resistance mutations to other classes of agents do not appear to place any selective pressure on viral envelope genetics and the risk for diminished susceptibility to CCR5 inhibitors. Indeed, their efficacy appears so far to be primarily determined by the absence of CXCR4-using variants.

Summary

As the first in a new class of oral entry inhibitors, maraviroc has demonstrated sustained HIV suppression in both treatment-experienced and treatment-naïve patients when combined with other active agents. Although candidates for maraviroc and other CCR5 inhibitors must be screened to confirm CCR5-only virus, approximately 80% of patients are expected to respond to these agents based on virus type. New, more sensitive assays are improving the likelihood that CXCR4-variant infections will be excluded. The clinical significance of the greater CD4+ cell increase achieved with CCR5 inhibitors relative to other agents is still being evaluated, but the high degree of tolerability and the evidence so far of sustained safety make these agents viable for use in routine practice.

References

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

2. Lalezari et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003;348:2175-85.

3. Walmsley et al. Treatment response to ritonavir-boosted lopinavir in HIV-1 patients with higher lopinavir mutation scores. AIDS 2007;21:2245-8.

4. Saag et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV] / lamivudine [3TC]), for the treatment of antiretroviral naïve patients infected with R5 HIV-1: week 48 results of the MERIT study. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract WESS104.

5. Saag et al. Reanalysis of the MERIT study with the enhanced Trofile assay. ICAAC 2008. Washington, DC. October 25-28, 2008. Abstract H-1232a.

6. Zingman et al. Vicriviroc, a next generation CCR5 antagonist, exhibits potent, sustained suppression of viral replication in treatment-experienced adults: VICTOR-E1 48-week results. CROI 2008. Boston, MA. February 3-6, 2008. Abstract 39LB.