Patients with CXCR4-tropic or Dual/mixed-tropic HIV Experience Earlier Treatment Failure on Maraviroc than Those with CCR5-tropic Virus

By Liz Highleyman

Researchers from Pfizer presented data on co-receptor tropism changes among patients receiving the CCR5 antagonist maraviroc (Selzentry) at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy this week in Chicago.

CCR5 antagonists block the CCR5 co-receptor, one of the 2 co-receptors HIV-1 uses to enter cells. In order to enter, the virus must bind to both the CD4 receptor and either the CCR5 or CXCR4 co-receptor. CCR5 antagonists work against CCR5-tropic virus, but should not be used by people with CXCR4-tropic or dual/mixed-tropic virus. Dual-tropic HIV strains can use either co-receptor, while mixed-tropic indicates that a person has a virus population that contains both CCR5-tropic and CXCR4-tropic strains.

Inhibition of virus entry of CCR5-utilizing (monocytotropic) and CXCR4-utilizing (T-cell tropic) HIV isolates by the natural ligands of the chemokine coreceptors CCR5 and CXCR4.

In general, CCR5-tropic HIV predominates during early infection, while CXCR4-tropic virus typically appears during later stages and is associated with more advanced disease. Some experts have expressed concern that using a CCR5 antagonist might suppress CCR5-tropic virus and thereby encourage the emergence of CXCR4-tropic strains. But studies have shown that after withdrawal of maraviroc, CCR5-tropic virus re-emerges as the dominant population, with reversion taking about 16 weeks.

The Pfizer investigators looked at changes in co-receptor tropism among participants in the MOTIVATE 1 and MOTIVATE 2 trials. These were identical randomized, controlled studies in which highly treatment-experienced patients with triple-class antiretroviral resistance were randomly assigned to receive oral maraviroc at doses of 150 mg once-daily (QD) or 150 mg twice-daily (BID), or else placebo, in combination with an optimized background regimen.

The 24-week data from these trials* were presented at the Retrovirus conference this past February, and 48-week data were presented in Chicago this week.**

Tropism was determined using the Monogram Biosciences Trofile assay. for samples from patients who experienced virological failure while taking maraviroc and had a viral load > 500 copies/mL. Samples were classified as only CCR5-tropic virus detected, only CXCR4-tropic virus detected, dual/mixed-tropic (D/M-tropic) virus, or NR/NP (not reportable/non-phenotypable). Tropism results were correlated with CD4 cell count, time to treatment failure, and category C HIV disease events.

Results

• Of 751 maraviroc-treated patients with CCR5-tropic virus at baseline, 63 failed with D/M or CXC4-tropic virus, compared to 35 with CCR5-tropic virus.

• Time to failure with a D/M or CXCR4-tropic virus was approximately 30 days shorter than for failure with a CCR5-tropic virus.

• Patients failing on maraviroc had a larger mean increase in CD4 cell count (49 cells/mm3 in the QD arm and 71 cells/mm3 in the BID arm) compared with placebo (14 cells/mm3).

• This remained true for subjects who had D/M or CXCR4-tropic virus at time of maraviroc failure (37 cells/mm3 QD and 56 cells/mm3 BID).

• For maraviroc-treated patients with D/M or CXCR4-tropic virus and with in-study but off-drug follow up data, 30 of 44 (68%) had CCR5-tropic virus at their last visit (median = 203 days).

• The median time of follow-up was significantly shorter for patients with D/M or CXCR4-tropic virus at their last visit.

• There was no association between CXCR4-tropic virus and category C AIDS events.

Conclusion

"These data are consistent with the selective and reversible suppression of CCR5-tropic viruses during maraviroc therapy resulting in detection of D/M or [CXCR4]-tropic virus at time of failure in two thirds of patients," the investigators concluded. "Patients failing a maraviroc regimen had higher mean CD4 increases even in the context of D/M or [CXCR4]-tropic virus."

09/21/07

References

E Van der Ryst and M Westby. Changes in HIV-1 Co-Receptor Tropism for Patients Participating in the Maraviroc Motivate 1 and 2 Clinical Trials. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, September 17-20, 2007. Abstract H-715.

*M Nelson, G Fatkenheuer, I Konourina, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia and North America: 24 week results. 14th Conference on Retroviruses and Opportunistic Infections (14th CROI). Los Angeles, February 25-28, 2007. Abstract 104aLB.

*J Lalezari, J Goodrich, E DeJesus, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24 week results from a phase 2b/3 study in the US and Canada. 14th CROI. Los Angeles, February 25-28, 2007. Abstract 104bLB.

**J Lalezari and H Mayer (for the MOTIVATE 1 Study Team). Efficacy and Safety of Maraviroc (MVC) in Antiretroviral Treatment-Experienced Patients Infected with CCR5-Tropic HIV-1: 48-Week Results of MOTIVATE 1. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (47th ICAAC). Chicago, September 17-20, 2007. Abstract H-718a.