Maraviroc results in R5/X4 mixed/dual tropic patients: unexpected safety data shows possible immunolocical effect
Simon Collins, HIV i-Base
Of the three CCR5 inhibitors in development last year, only the Pfizer compound (maraviroc) is showing continued promise as a treatment for both naive and treatment experienced patients. [1, 2]
The rationale for studying maraviroc (MVC) 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). 
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
|Placebo + OBT n=62||MVC QD + OBT n=63||MVC BID + OBT n=61|
|Mean age (yrs), (range)||44.6 (23-65)||42.7 (16-59)||42.5 (16-62)|
|Female, n (%)||9 (14.5)||10 (15.9)||6 (9.8)|
|Race, n (%)|
|White||40 (64.5)||46 (73.0)||44 (72.1)|
|Black||18 (29.0)||17 (27.0)||13 (21.3)|
|Other||4 (6.5)||0 (0)||4 (6.6)|
|(min, max)||(2, 650)||(1, 442)||(0, 615)|
|HIV-1 RNA (log10 copies/mL)|
|(min, max)||(3.65, 6.15)||(3.42, 5.94)||(3.61, 6.67)|
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
|All treated patients with D/M-tropic HIV-1||Placebo + OBT n=58||MVC QD + OBT n=57||MVC BID + OBT n=52|
|Mean decrease in HIV-1 RNA (log10 c/mL)*||-0.97||-0.91||-1.20|
|Treatment diff (MVC – OBT) in HIV-1 RNA decrease (log10 c/mL) (97.5% CI)||–||+0.06 (-0.53, +0.64)||-0.23 (-0.83, +0.360|
|RNA <400 c/mL (%)||24.1||24.6||30.8|
|RNA <50 c/mL (%)||15.5||21.1||26.9|
|Mean decrease in RNA in pts using T-20** (log10 c/mL)||-0.89||-1.26||-1.44|
|Mean CD4 change (cells/mm3)||+36 (n=58)||+60 (n=57)||+62 (n=52)|
|Pts with only X4-tropic HIV-1 detectable at time of virologic failure|
|Mean CD4 change (cells/mm3)||-104 (n=2)||+48 (n=12)||+33 (n=12)|
There were 13 category C events: MVC QD (7), MVC BID (3), placebo (3). None of the 7 deaths in the study (MVC QD (2), MVC BID (2), placebo (3) were considered MVC-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
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.
- GSK closes Phase 3 studies of its CCR5 inhibitor aplaviroc and terminates development programme. HIV Treatment Bulletin, Nov/Dec 2005.
- Schering discontinues Phase II studies of vicriviroc in treatment naive patients. HIV Treatment Bulletin, Nov/Dec 2005.
- 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.