New analyses from ongoing clinical trials have confirmed that maraviroc-containing treatment is more likely to fail in people who have developed X4-tropic or dual/mixed tropic virus in addition to the CCR5-tropic virus that maraviroc was designed to suppress. However, CD4 cell counts were found to be higher even in people who experienced maraviroc treatment failure, and if maraviroc teratment ceased in those who experienced a tropism shift, the virus population was observed to shift back to R5 tropism within one month in almost all cases. These findings were presented at an oral session at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago this week.
The CCR5 antagonist maraviroc (Celsentri) is being studied in two ongoing clinical trials (MOTIVATE 1 and 2) in treatment-experienced patients. In these randomised phase II/III trials, patients received an optimised background therapy (OBT) combination selected according to resistance profiles. A control group received OBT only, while the study group also received maraviroc (at 300mg once daily, or 150mg twice daily).
The studies differ only by geography: MOTIVATE 1 recruited patients from Canada and the US; MOTIVATE 2 studied patients from Europe and Australia as well as North America.
When combined with optimised background therapy (OBT), maraviroc has demonstrated statistically significantly greater virologic suppression at 24 weeks compared to OBT alone. These virologic results have been reported at previous conferences.
The aim of the analysis presented at the 47th ICAAC was to study how HIV viral tropism was affected by failure of maraviroc treatment.
Tropism, determined using Monogram Biosciences' Trofile™ assay, was reported as: R5-tropic (only CCR5-tropic virus detected), X4-tropic (only CXCR4-tropic virus), dual/mixed-tropic, or NR/NP (not reportable/non-phenotypable). These differently-tropic viral strains were then correlated with CD4 cell count, time to virologic failure, and category C (AIDS-defining clinical) events.
Overall, more treatment failures occurred, and they occurred more quickly, in people who developed shifts away from purely R5-tropic virus. At baseline, 751 maraviroc-treated patients had purely R5-tropic virus. Of these, 63 treatment failures occurred in people who had developed X4-tropic or dual/mixed virus, compared to 35 failures in people who still displayed only R5-tropic virus. Time to failure with an X4 or dual/mixed virus was approximately 30 days shorter than for failure with R5-tropic virus. There was no association between CXCR4-using virus and category C events.
As maraviroc can only interfere with the binding of R5-tropic virus by blocking the CCR5 coreceptor, it is unsurprising that treatment failure would be associated with the emergence of X4- or dual-tropic virus. However, in a less expected finding, increases in CD4 cell counts were still seen even if maraviroc treatment failed virologically.
Patients on the maraviroc-plus-OBT regimen had, at the time of virologic failure, CD4 cell count increases of 49 cells/mm3 (on the once-daily dose) and 71 cells/mm3 (on the twice-daily dose), compared to increases of 14 cells/mm3 for those on OBT alone.
Looking only at those participants who failed with X4- or dual/mixed-tropic virus, CD4 cells were still elevated at failure, although to a somewhat lesser degree (37 cells/mm3 on the once-daily dose, 56 cells/mm3 on the twice-daily dose).
The researchers also looked at whether viral tropism reverted to R5 in patients who had experienced a tropism shift and then stopped maraviroc treatment. In 14 patients who experienced a switch, the virus reverted to R5 tropism after a median of 16 days off maraviroc.
The study researchers concluded that "these data are consistent with the selective and reversible suppression of CCR5-tropic viruses during maraviroc therapy resulting in detection of dual/mixed or X4-tropic virus at time of failure in two thirds of patients. Patients failing a maraviroc regimen had higher mean CD4 increases [than those not taking maraviroc] even in the context of dual/mixed or X4-tropic virus".
van der Ryst E et al. 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, abstract H-715, 2007.