Maraviroc results in R5/X4 mixed/dual tropic patients: unexpected safety data shows possible immunolocical effect
10 September 2006. Related: Conference reports, Antiretrovirals, World AIDS 16 Toronto 2006.
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). [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
| 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) |
| Tropism, n | |||
| X4 | 2 | 2 | 4 |
| R5 | 0 | 1 | 0 |
| NP/NR | 2 | 3 | 5 |
| D/M | 58 | 57 | 52 |
| CD4 (cells/mm3) | |||
| Mean | 99 | 85 | 96 |
| Median | 42 | 40 | 43 |
| (min, max) | (2, 650) | (1, 442) | (0, 615) |
| HIV-1 RNA (log10 copies/mL) | |||
| Mean | 5.01 | 5.03 | 5.10 |
| Median | 5.10 | 5.10 | 5.17 |
| (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
Comment
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:
- 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/3106 - Schering discontinues Phase II studies of vicriviroc in treatment naive patients. HIV Treatment Bulletin, Nov/Dec 2005.
http://www.i-base.info/htb/3111 - 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.