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PRIORITY PRESS - 7th European HIV Drug Resistance Workshop

Stockholm, Sweden / March 25-27, 2009

It is reasonable to expect antiretroviral agents that block target cell entry via the R5 receptor to be less effective against infection that can also gain entry through the X4 receptor. However, in infection with dual or mixed (DM) tropism, the reduction in efficacy has been found to be relative, not absolute. In the phase III registration trials with maraviroc, the first R5 entry inhibitor to be approved for routine clinical use, 45% of the patients who were subsequently found to have DM virus achieved complete viral suppression (<50 copies HIV RNA/mL).

A European consensus group citing these data concluded that rejecting R5 inhibitors based on the newer, more sensitive assays for X4 chemokine receptor tropism might not be appropriate in the event of diminishing treatment options. “The Working Group suggests that tropism guidelines should not impose restrictions for the use of CCR5 inhibitors in patients with an urgent need for a new drug class,” reported Dr. Linos Vandekerckhove, AIDS Reference Centre, Ghent University Hospital, Belgium. Leader of the European Consensus Group on Clinical Management of Tropism Testing, Dr. Vandekerchkhove conceded that tropism should be tested, particularly because of the correlation between the presence of R5-only virus and complete viral suppression in the R5 registration trials, but he indicated that the concept that dual tropic virus precluded use of a R5 inhibitor would now appear overly simplistic.

R5 and X4 Co-Receptors

HIV infects target cells by attaching via either the R5 or the X4 co-receptor. Early in infection, most HIV is R5-tropic, meaning the R5 receptor is employed exclusively. Infections that exhibit exclusive X4 tropism early in the disease course are rare, so almost all other infections are capable of employing both receptors. Some of these are mixed tropic (MT), meaning some of the isolated virions use the R5 receptor and others use the X4, but most are dual tropic (DT), meaning the isolates are capable of using either receptor. However, DT does not mean that R5 and X4 receptors are used with equal efficacy.

“Among primary isolates from clinical specimens, DM-tropic viruses are mostly constituted by a swarm of species with DT potential rather than mixtures of R5- or X4-using viruses,” according to Dr. Valentina Svicher, Department of Experimental Medicine, University of Rome (Tor Vergata), Italy. She reported that two DT categories have been recently identified. These are DT strains that use the R5 receptor more efficiently than X4, and the DT strains that use the X4 receptor more efficiently than R5. Of these, the DT strains preferentially employing R5 appear to be more common, which has important implications for CCR5 blockers.

CCR5 Blocker Activity in Dual or Mixed Infection

In experimental work by Dr. Svicher, the in vitro activity of the CCR5 inhibitor maraviroc was evaluated in DM HIV isolates with the goal of studying its activity in the presence of virus with the capability of X4 attachment. Consistent with the phase III studies associating maraviroc with full viral suppression in almost half of the patients with DM isolates, “maraviroc fully inhibited the replication of mixed R5/X4-tropic isolates with X4 virus as a minority species. No emergence of X4 virus was observed in up to seven co-cultures [that were maintained] over two months,” Dr. Svicher reported. Much like the European Consensus Guidelines Writing Group, Dr. Svicher indicated her findings support the possibility that “the use of maraviroc in patients infected with DT virus can be a therapeutic option that deserves further attention.”

However, this does not eliminate the need to evaluate chemokine tropism when initiating R5 inhibitors, particularly in treatment-naïve patients. In the MERIT (Maraviroc vs. Efavirenz Regimens as Initial Therapy) study, which was a non-inferiority trial that randomized previously untreated HIV infected patients to maraviroc 300 mg b.i.d. or efavirenz 600 mg q.d. (both agents in combination with zidovudine and lamivudine in a co-formulation), the CCR5 blocker was initially found slightly less effective for complete viral suppression than efavirenz (65.3% vs. 69.3%). Although all patients were screened for the presence of R5 virus, the assay initially employed had relatively poor sensitivity for X4 virus. When the data were reanalyzed using a more sensitive assay, the patients who had low levels of X4 virus undetected by the original assay were removed from the analysis, and the rates of complete viral suppression were exactly the same (68%). Despite similar viral suppression, maraviroc was more effective for immune reconstitution (+170 cells/mm³ vs. +144 cells/mm3).

Response rates with maraviroc appear optimal in patients with R5-tropic virus but again, the presence of dual tropism does not preclude benefit. In the MOTIVATE (Maraviroc vs. Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients) trials, which randomized highly treatment-experienced patients to maraviroc (150 mg q.d. or 150 mg b.i.d). or placebo (all patients received an optimized background treatment [OBT] regimen), almost 10% of the participants had DM at baseline. In these, 30% of the q.d. maraviroc patients vs. 18% of controls achieved and maintained complete viral suppression. Success rates may have been even higher in those with two or more active drugs in the OBT based on a recent re-analysis.

Option of Genotyping

“Initiation of therapy combining two or more potent drugs with maraviroc b.i.d. was associated with 78% [of patients] at <50 copies/mL at 48 weeks,” reported Dr. Charles Boucher, Utrecht University, The Netherlands. Although his analysis with a genotypic weighted OBT score (g-wOBTS) did not take into account tropism at baseline, it did evaluate tropism at study end. It demonstrated that tropism evolution leading to virologic failure depended heavily on the potency of the background regimen. This suggests that when an effective R5 inhibitor is combined with other potent agents, the pressure for a switch in tropism remains low.

Currently, the most effective tropism assay approved for use is Trofile. While it is highly sensitive, a faster turnaround time would be beneficial. Several genotyping methods based on characterizing the V3 loop of the envelope protein have entered clinical studies and may be more practical for some applications. Genotyping is attractive because it is relatively inexpensive and it can be performed in the same laboratories now performing genotypic drug resistance, promising more rapid results. In one study that evaluated a gp120 V3 genotyping method in 45 patients already evaluated with the enhanced Trofile (Trofile ES) method, results were considered promising.

Based on a performance that compared favourably with the Trofile ES for several end points, the gp120 V3 assay “may be applied for tropism genotyping in samples with a low viral load not testable for Trofile, in negative results with Trofile, and in monitoring follow-up of Trofile [assessed] R5 patients treated with CCR5 antagonists,” suggested Dr. Andrea DeLuca, Catholic University, Rome. She remarked that the availability of quicker and cheaper assays for R5 tropism would likely greatly accelerate use of R5 inhibitors, which have the advantages of a favourable safety profile and low risk of generating resistance to alternative antiretroviral agents.

Summary

Conceptually, entry inhibitors represent an important and revolutionary concept in antiretroviral drug treatment. These agents prevent virus from entering target cells that block the virion reproduction that leads to mutations and resistant disease. In practice, these agents have been highly effective in both treatment-experienced and treatment-naïve HIV-infected patients. Although R5 inhibitors can be expected to be most effective for R5-tropic infection, data with maraviroc suggest that this agent retains the ability to achieve full viral suppression (<50 copies/mL) even in R5/X4 DT virus, a potentially important finding for treating treatment-experienced patients with diminishing therapeutic options.