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Update on data presented during the 15th Conference on Retroviruses and Opportunistic Infections

Boston, Massachusetts / February 3-6, 2008

Successful treatment of HIV infection requires long-term suppression of viral replication and the restoration and preservation of immunologic function, which in turn improve patients’ survival and quality of life. The established anti-HIV armamentarium now includes numerous agents that inhibit enzymes vital to HIV replication, as well as inhibitors of virus cell entry and fusion. Ongoing research efforts are aimed at discovery of novel agents and combinations that can thwart the virus’s capacity for mutation and resistance to previously effective therapies.

In the early stages of infection, HIV populations are relatively homogeneous. Over time, however, the virus typically develops myriad mutations leading to drug resistance. In treatment-experienced individuals, therefore, highly individualized therapy becomes more important. Still, even highly treatment-experienced patients can achieve undetectable viral DNA with an optimized antiretroviral regimen. Current guidelines recommend the administration of two or three active agents including those from the newest therapeutic classes.

Role of Tropism Testing

In patients who have experienced failure of antiretroviral therapy, the selection of an appropriate new regimen must take into account genotypic testing and prior drug history to establish resistance patterns, remarked Dr. Anita Rachlis, Professor of Medicine, Division of Infectious Diseases, Sunnybrook Health Sciences Centre, University of Toronto, Ontario. In addition, testing for tropism allows identification of the virus’s preferred point of entry to CD4+ cells—the CCR5 or CXCR4 chemokine coreceptor (or both)—and thus suggests an optimal mechanism and agent for viral entry inhibition. Approximately 40% to 60% of treatment-experienced patients have exclusively CCR5-tropic virus, while some 20% to 40% have dual- or mixed-tropic HIV and a much smaller proportion have exclusively CXCR4-using HIV (Figure 1).

Figure 1. Virus Point of Entry

As discussed in presentations at this year’s CROI, tropism testing with the Trofile assay has been a crucial component of studies of CCR5 coreceptor antagonists including maraviroc and the investigational agent vicriviroc. Because these agents cannot inhibit replication of HIV which enters via the CXCR4 coreceptor (and the presence of CXCR4 virus has been associated with reduced antiviral activity in patients using CCR5 antagonists), therapy with maraviroc or vicriviroc should be employed only in patients whose HIV is solely CCR5-tropic. Similarly, in clinical practice, the Trofile test assists selection of an optimized anti-HIV regimen and is required to determine whether CCR5 inhibition with maraviroc is an option.

Assay Sensitivity Enhanced

Recently, the Trofile test was improved to heighten its sensitivity to very low levels of CXCR4-using virus, while maintaining infection specificity. According to an announcement by the manufacturer, it is now 100% sensitive at detecting CXCR4 minor variants that comprise as little as 0.3% of the total viral population. This sensitivity represents a 30-fold increase over that of the initial assay (in use since the autumn of 2007), which had 100% accuracy when CXCR4 variants made up at least 10% of the total viral population and 83% accuracy at a level of 5%. In practice, the improvement allows the capture of an additional 8% to 10% of patients whose virus enters cells via the CXCR4 rather than CCR5 coreceptor. As such, it enhances the treating physician’s assurance that a CCR5 inhibitor is an appropriate component of the patient’s antiretroviral regimen. These developments are important as they “can refine the group of patients for which maraviroc will be an appropriate choice,” confirmed Dr. Rachlis. There are no changes to the procedures employed for Trofile or in minimal viral load requirements.

The approval and use of maraviroc has to date been guided by the MOTIVATE (Maraviroc Plus Optimized Background Therapy in Viremic, ART-Experienced Patients) studies, which used the earlier version of the Trofile assay. In these studies, from which 48-week data were presented here, significantly more patients receiving maraviroc than placebo in addition to optimized backbone therapy achieved HIV-RNA of <400 copies/mL (56.1% of patients taking maraviroc b.i.d. and 51.7% of those taking the agent once daily vs. 22.5% of those receiving only optimized backbone therapy). An even greater effect was observed when an HIV-RNA target of <50 copies/mL was used (45.5% and 43.2% for maraviroc b.i.d. and once daily, 16.7% for placebo). Similarly, patients receiving active therapy vs. placebo experienced a greater increase in CD4+ cell counts (up to 124 cells/m3 vs. 61 cells/m3). “The degree to which the higher-sensitivity Trofile assay would have altered the results of these trials is unknown but it may have improved the identification of patients with CCR5-tropic HIV and excluded those with mixed or dual tropic virus in whom the response could have been expected to be less favourable,” Dr. Rachlis observed. Additional prospective studies of a treatment regimen including maraviroc, in tandem with patient selection with the heightened sensitivity Trofile assay, are in progress.

An initial re-analysis of the results of the MERIT study, which failed to demonstrate the non-inferiority of maraviroc vs. efavirenz (based on achievement of HIV-RNA <50 copies/mL) in treatment-naive patients, was presented here at CROI (Heera et al., Abstract 40LB). It determined that 25 patients (3.5%) had dual/mixed tropic virus at baseline although they were identified as having CCR5-tropic HIV at screening. As would be expected, the response to maraviroc was low in this subgroup (7.1% at 48 weeks). However, the proportion of maraviroc-treated individuals with CCR5 tropism achieving HIV RNA <50 copies/mL increased to 68% from 65.3% in the initial MERIT report. This research also showed that tropism changes 50% less frequently with clade C than other clades. Further re-analysis of samples from MERIT using the enhanced-sensitivity Trofile test is expected later this year and may provide support for highly accurate tropism profiling to guide therapy in this patient subset.

Patients who are currently taking the CCR5 antagonist based on earlier Trofile testing need not be retested, unless viral suppression is inadequate and a change in treatment regimen is contemplated, indicated Dr. Rachlis. Recommendations for repeat tropism testing or monitoring during maraviroc treatment have not yet been established.

Summary

Improved measures to tailor and target antiretroviral therapy are welcome news to physicians and their patients, Dr. Rachlis concluded. “The increased sensitivity [of this assay] and the potential development of other methods of identifying tropism can only be beneficial.”