Maraviroc results in R5/X4 mixed/dual tropic patients: unexpected safety data shows possible immunolocical effect

HIV Treat Bull - Vol. 7, No. 7/8, September 2006

Of the three CCR5 inhibitors in development last year, only the Pfizer compound (maraviroc) is showing continued promise as a treatment for both naïve and treatment experienced patients. [1, 2]

The rationale for studying maraviroc (MRV) in patients with dual/mixed (D/M)-tropic infections includes the theoretical risk of outgrowth of X4-tropic HIV-1 when a patient with D/M-tropic HIV-1 is treated with a CCR5 antagonist and because X4-tropic HIV-1 has been associated with more rapid CD4 cell depletion and progression to AIDS.

Mayers and colleagues presented results from a double-blind placebo controlled study in 190 mixed/dual tropic patients who were randomised to optimised background regimen (OBT) including at least one sensitive drug, plus either maraviroc once-daily (n=63), maraviroc twice daily (n-61) or placebo (n-60). [3]

Over 90% patients were PI-experienced, with 50-60% currently using T-20. CD4 count and viral load were <100 cells/mm³ and > 5logs respectively. >95% patients had dual/mixed tropism. Further baseline characteristics and tropism are detailed in Table 1.

Table 1: Baseline characteristics and tropism

After 24 weeks, the mean decrease in viral load was similar between the maraviroc and placebo arms, but there was a statistically significant increase in CD4 counts in the maraviroc groups compared to placebo, which are detailed in Table 2.

Table 2: Virologic and immunologic responses at week 24

There were 13 category C events: MRV QD (7), MRV BID (3), placebo (3). None of the 7 deaths in the study (MRV QD (2), MRV BID (2), placebo (3) were considered MRV-related.

The study concluded that over 24 weeks, in treatment-experienced patients with D/M-tropic HIV-1 and advanced disease, maraviroc + OBT was generally well tolerated. There were no cases of hepatotoxicity, lymphoma or adenocarcinoma. Although the treatment arms did not demonstrate superior reductions in HIV-1 RNA compared with placebo, maraviroc + OBT was associated with greater increases in CD4 cell count than placebo + OBT.

Patients receiving maraviroc + OBT were more likely to fail with X4-tropic HIV-1 than those receiving placebo + OBT. However, patients treated with maraviroc and X4-tropic virus at treatment failure had increases in CD4 cell count consistent with the overall maraviroc-treated population

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While virological response in this study was similar to placebo, this was expected in dual-tropic patients. More significant is the lack of HIV progression in this group, which was the main safety concern.

The safety from short-term exposure to a CCR5 inhibitor in patients with mixed tropism at baseline, may also indicate a lower dependence on a tropism test prior to treatment, especially as the current test is relatively insensitive and expensive.

The CD4 increase in the maraviroc arm was unexpected and deserves further investigation.

References

1. GSK closes Phase 3 studies of its CCR5 inhibitor aplaviroc and terminates development programme. HIV Treatment Bulletin, Nov/Dec 2005.
http://www.i-base.info/htb/v6/htb6-11-12/aplaviroc.html
2. Schering discontinues Phase II studies of vicriviroc in treatment naïve patients. HIV Treatment Bulletin, Nov/Dec 2005.
http://www.i-base.info/htb/v6/htb6-11-12/vicriviroc.html
3. Mayer H, van der Ryst E, Saag M et al. Safety and efficacy of maraviroc, a novel CCR5 antagonist, when used in combination with optimised background therapy for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. IAS Toronto, 2006. Abstract late breaker THLB0215.

2006-09-10
IB060709-07

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