July 25, 2007
Information on CCR5 entry inhibitors continues to be of great interest at recent international HIV conferences, including the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007) in Sydney where we witnessed the unveiling of results from the maraviroc (MVC, Selzentry) treatment-naive trial.
At the 14th Conference on Retroviruses and Opportunistic Infections (CROI 2007) last year in Los Angeles, we saw the presentation of the results of the MOTIVATE 1 and 2 studies.1,2 In these studies, the efficacy and safety of maraviroc in heavily treatment-experienced CCR5-tropic patients were compared to that of a placebo. These studies demonstrated that maraviroc -- at each of the two doses tested -- combined with an optimized background regimen (OBR) was very active. There was an average decline in HIV-1 RNA of approximately 1.9 log10 copies/mL from baseline at week 24 in both treatment arms, and this was 10 times the viral suppression seen with the placebo plus OBR arm.
That data from the MOTIVATE studies clearly showed the benefit of adding a fully active drug, such as a CCR5 entry inhibitor, to the treatment regimen of patients with a high degree of resistance. But it was unknown if this entry inhibitor would benefit the treatment-naive population. The MERIT Study3 was specifically designed to answer this very question: Can we use maraviroc, instead of efavirenz (EFV, Sustiva, Stocrin), combined with a nucleoside backbone in treatment-naive patients?
MERIT is an ongoing phase 2B/3 double-blind study, in which maraviroc (300 mg twice daily) is being compared to efavirenz, both in combination with a zidovudine/lamivudine (AZT/3TC, Combivir) backbone, in treatment-naive CCR5-tropic HIV-1 patients.
Patients were stratified at screening according to whether they had a baseline viral load of less than or more than 100,000 copies. Originally, there was also a once-daily maraviroc arm, but that was discontinued at week 16 due to underperformance during a planned analysis.
The study allowed the substitution of zidovudine (AZT, Retrovir) with an alternative nucleoside reverse transcriptase inhibitor (NRTI) for the management of any zidovudine-related toxicity. This is significant since we know that zidovudine-containing regimens in treatment-naive patients are traditionally associated with some degree of discontinuation due to adverse events.
The following graph summarizes the study results for the proportion of patients achieving a viral load of less than 50 copies.
The results of this study were significant in that efavirenz slightly outperformed maraviroc. Although maraviroc proved to be non-inferior to efavirenz according to the less-than-400-copies analysis (70.6% versus 73.1%, not shown in graph), it did not prove non-inferior in the less-than-50-copies analysis (65.3% versus 69.3%).
The relevance of those differences can be better appreciated when we look at the stratification results by baseline viral load, according to which clearly there was a larger difference in responses at a baseline viral load greater than 100,000 copies. This suggests a possible difference in potency between these regimens -- similar to what we have seen in the past with the use of non-boosted protease inhibitors (PIs) or even the triple nucleoside combination of zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) in treatment-naive patients.
Part of the explanation regarding the difference observed between these two arms could be related to the proportion of patients who discontinued the study for various reasons. Although the percentage of participants who discontinued from the study prior to week 48 was similar in the maraviroc (26.9%) and efavirenz (25.2%) arms, the rate of discontinuations due to virologic failure was higher in the maraviroc arm (11.9%) compared to the efavirenz (4.2%) arm. On the other hand, the rate of discontinuation due to adverse events was lower with maraviroc (4.1%) than with efavirenz (13.6%). Lipids (total cholesterol, triglycerides and low-density lipoprotein cholesterol) were all neutral in patients treated with maraviroc, certainly an advantage over efavirenz.
So, to answer the question: Can we use maraviroc, instead of efavirenz, combined with a nucleoside backbone, in treatment-naive HIV-infected patients? The answer is yes, we can since there were decent responses seen in many of the patients treated with maraviroc plus two nucleosides. However, the second, and the most important, question would be: Why would we want to do that?
There was a disturbing underperformance seen in the maraviroc arm in this study, when compared to efavirenz, which could potentially be associated with the development of resistance in a treatment-naive patient population. The data on resistance for this study has not been presented, so we will have to stay tuned in to see what, if any, resistance consequences were paid by those patients who developed virologic failure of maraviroc.
With regard to the preference for using maraviroc to avoid efavirenz-associated central nervous system adverse events, it can be argued that there exists other proven simple PI regimens that, when used in treatment-naive patients, are not only very effective and tolerable, but are associated with a limited development of resistance in patients with virologic failure.
The lipid data observed in this study was reassuring, and pretty much resembled what we have seen with the integrase inhibitor raltegravir (RAL, MK-0518) in treatment-naive patients. While it certainly adds a bit of an advantage to maraviroc over efavirenz, the total sum of pros and cons does not appear to favor maraviroc.
Overall, there is no question of the immense value of maraviroc in the treatment-experienced population, but given the results of this treatment-naive trial, and maraviroc's current twice-daily dosing schedule, it is difficult to justify the use of this regimen in antiretroviral-naive patients, at least until more information is available to clarify why these difference in responses were observed.
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