July 25, 2007
CCR5 entry inhibitors, also called CCR5 chemokine receptor antagonists, are a new class of anti-HIV medication able to prevent new HIV infection in uninfected cells. It is designed to prevent HIV from entering uninfected CD4+ T cells by blocking the CCR5 receptor, which is needed for entrance. When a virus uses this type of receptor to enter into the cell, we call that virus "R5 tropic." Sometimes the virus is able to use a different chemokine receptor, such as the CXR4 receptor, to enter the cell, in which case we call that virus "X4 tropic." Occasionally a patient may be infected with virus able to use both receptors; this virus is known as "R5/X4-dual or R5/X4-mix." This is important, because CCR5 inhibitors only work in patients who have exclusively R5 virus. For patients with X4 or R5/X4 virus, these CCR5 entry inhibitors are not effective.
Information on CCR5 entry inhibitors as a way to treat HIV infection and AIDS continues to be of great interest at recent international HIV conferences. Maraviroc (MVC) is the CCR5 entry inhibitor furthest along in development. In the United States, maraviroc is already available under an expanded access program [click here to find out more] and it has been given an "approvable" status by the U.S. Food and Drug Administration (FDA), which means that it may soon become available for commercial use under the brand name Selzentry.
At the 14th Conference on Retroviruses and Opportunistic Infections (CROI 2007) in Los Angeles, Calif., this past February 2007, data was presented on two pivotal studies, MOTIVATE 1 and 2, conducted in heavily experienced HIV-infected patients who had failed several antiretroviral medications in the past and had accumulated significant resistance.1
In those studies, the efficacy and safety of maraviroc, in combination with an optimized background regimen (OBR) in R5-tropic, heavily experienced patients, were compared to that of placebo plus an OBR. The study showed that maraviroc -- at each of the two doses tested -- combined with an OBR, was very active. There was an average decline in HIV-1 RNA (viral load) of approximately 1.9 log10 copies/mL from baseline at week 24 in both maraviroc treatment arms. This response was 10 times better than the response seen with the placebo plus an OBR arm.
The MOTIVATE 1 (United States/Canada) and MOTIVATE 2 (Europe/Australia) studies are similar in design and enrolled similar types of patients. Results from each of the studies individually were very similar to each other, thus the data from those two studies can be combined together (called "pooled data") to conduct analyses that require a larger number of patients.
At the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007) in Sydney, Australia, two subanalyses2,3 of the pooled data from the two MOTIVATE studies were presented, which essentially confirmed some impressions that were already suggested by the individual study results.
In the first subanalysis,2 Roy Gulick and colleagues described the results of a planned 24-week analysis of the pooled data from both studies comparing the once-daily versus the twice-daily doses of maraviroc in different patient groups.
The overall results showed that maraviroc, given either once-daily or twice-daily, demonstrated statistically greater efficacy compared to placebo plus an OBR. Although the statistical analysis was not designed to directly compare the twice-daily and once-daily arms, this pooled analysis demonstrated similar safety profiles for twice-daily and once-daily arms versus the placebo arm (no increased hepatotoxicity or malignancy). On the other hand, there was a trend toward higher rates of virologic suppression with maraviroc twice-daily compared to maraviroc once daily.
|Placebo + OBR: %
||MVC QD + OBR: %
||MVC BID + OBR: %
|OVERALL||23% / 28% (N=209)||44% / 55% (N=414)||45% / 61% (N=426)|
|No active drugs in OBR (based on genotypic/phenotypic test results)||3% / 6% (N=35)||18% / 26% (N=51)||29% / 41% (N=56)|
|Baseline CD4+ cell count below 50 cells/mm3||3% / 5% (N=37)||11% / 20% (N=85)||20% / 31% (N=85)|
|Screening HIV-1-RNA >100,000 copies/mL||11% / 16% (N=84)||28% / 45% (N=170)||35% / 52% (N=176)|
These differences in efficacy were mostly seen in subgroup analysis, which revealed a greater benefit from a twice-daily dosing in certain populations, including patients with a baseline viral load greater than 100,000 copies/mL and patients with a CD4+ cell count less than 50 cells/mm3.
So it is clear that maraviroc has a role in the treatment of HIV infection, especially in the treatment-experienced population. We do not know yet when the drug will become available and what the FDA-approved dose will be. But given that this drug has the potential to be administered at various dosages, it is important that we pay attention to the subtle difference in responses seen in these groups, and that we consider tailoring the dose used to maximize the patient's response.
The second subanalysis3 from these MOTIVATE studies was conducted to evaluate the efficacy of maraviroc when combined with an OBR containing at least one potent antiretroviral (either enfuvirtide [T-20; Fuzeon], lopinavir/ritonavir [LPV/r, Kaletra], tipranavir [TPV, Aptivus], fosamprenavir [FPV, 908, Lexiva, Telzir] or atazanavir [ATV, Reyataz]) that the patient had never used before. Darunavir (TMC114, Prezista) was not permitted as it was only available under expanded access at the time this study was being conducted.
The study investigators used the GSS (Genotypic Susceptibility Score) to indicate the total number of drugs in the OBR to which the patient's viral isolate showed wide-type genotypic sensitivity at screening.
This analysis of the efficacy of maraviroc when combined with another active drug in an OBR, showed that more patients with a higher susceptibility score reached an undetectable viral load than those with a lower score. For example, patients receiving maraviroc who had no enfuvirtide or lopinavir/ritonavir resistance, had an increased likelihood of achieving an undetectable viral load, which is consistent with what we have seen with other similar studies.
The results demonstrated the additional treatment benefit of including a potent new drug as part of an OBR when initiating treatment in patients who are known to have significant resistance.