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New Classes, New Agents: Changing the Paradigm of Antiretroviral Treatment?

Raltegravir (the first integrase inhibitor) and maraviroc (the first CCR5 inhibitor) are both effective and well tolerated in highly treatment-experienced patients.

Investigators at the 14th Retrovirus Conference presented compelling data from international phase III studies of two new drugs from two new classes: raltegravir (the first integrase inhibitor) and maraviroc (the first CCR5 inhibitor). Both drugs are highly effective in patients with extensive treatment failure, are likely to have similar activity in treatment-naive individuals, are well tolerated, and do not require pharmacokinetic boosting with ritonavir. The results presented here in treatment-experienced patients are so promising that these agents may upend the current paradigm of two NRTIs plus a boosted PI or NNRTI for HIV treatment.

Raltegravir

In the BENCHMRK-1 and -2 trials, 699 heavily treatment-experienced patients (mean viral load, 4.6 log copies/mL; mean CD4 count, about 150 cells/mm³) were randomized to receive an optimized background regimen plus either raltegravir (400 mg twice daily) or placebo [Abstracts 105aLB and 105bLB]. Background regimens typically consisted of three drugs, which could include T-20 and darunavir. Approximately 20% of patients had genotypic or phenotypic susceptibility scores of 0, meaning that none of the drugs in their background regimen were predicted to have any activity, and approximately 33% had susceptibility scores of 1, including new use of darunavir or T-20. Approximately 20% of patients in both studies used T-20 as a new drug in their background regimens; darunavir was used more frequently in BENCHMRK-2 than in BENCHMRK-1 (about 50% vs. 25%).

In a combined intent-to-treat analysis at 16 weeks, 79% of raltegravir recipients had achieved viral loads <400 copies/mL, compared with 43% of placebo recipients. Viral decay was much faster than previously documented for other agents; by week 2, most subjects who would achieve viral loads <400 copies/mL had already done so. Interestingly, this salvage study is the first to show that receipt of other new agents, such as T-20 and darunavir, did not add significantly to virologic response; without either of these drugs, 74% of raltegravir recipients achieved viral loads <400 copies/mL, compared with 29% of placebo recipients. As predicted by in vitro studies, three mutations were associated with virologic failure in the raltegravir group: N155H, Q148K/R/H, and Y143R/C. Raltegravir was very well tolerated, with less than 2% of subjects discontinuing treatment because of adverse events.

Maraviroc

In parallel to the raltegravir studies, MOTIVATE-1 and -2 are identical phase III studies of the CCR5 inhibitor maraviroc [Abstracts 104aLB and 104bLB]. A total of 1076 heavily treatment-experienced patients with CCR5-tropic virus and viral loads 5000 copies/mL (median, 4.8 log copies/mL; median CD4 count, about 165 cells/mm³) were randomized to receive optimized background therapy plus either maraviroc (150 mg once daily or 150 mg twice daily) or placebo. Approximately 40% of all study participants received T-20 as part of their background regimens. About two thirds of all participants had genotypic or phenotypic susceptibility scores of 2.

In a 24-week intent-to-treat analysis in MOTIVATE-2, the mean decrease in viral load from baseline was about 1.95 log copies/mL in the maraviroc arms and 0.93 in the placebo arm. Viral-load results diverged at week 2 and continued to do so through week 24. The proportion of patients with viral loads <400 copies/mL was 56% in the once-daily maraviroc arm, 61% in the twice-daily maraviroc arm, and 23% in the placebo arm. All these differences were highly statistically significant and were similar to those seen in MOTIVATE-1. In a combined analysis from the two studies, the proportion of patients who achieved viral loads <50 copies/mL despite a susceptibility score of 0 was 18% in the once-daily maraviroc arm, 29% in the twice-daily maraviroc arm, and 3% in the placebo arm. For those with scores of 1, the proportions increased to 43%, 43%, and 9%, respectively, and for those with scores of 2, the proportions increased further to 52%, 53%, and 19%. Baseline viral loads 100,000 copies/mL were associated with poorer virologic responses in the placebo arm but not in the maraviroc arms; T-20 use did not markedly affect rates of response. The mean increase in CD4 count from baseline was twice as great in the maraviroc groups as in the placebo group (about 100 vs. 50 cells/mL). Maraviroc was well tolerated, with no excess diagnoses of malignancy.

Among those with virologic failure, substantially more patients in the maraviroc arms experienced coreceptor switches to CXCR4, and these individuals also had more modest CD4-cell increases. Thirty-five patients in whom maraviroc failed without a coreceptor switch still gained a considerable number of CD4 cells (mean, 61 cells/mm³ in the once-daily arm and 138 cells/mm³ in the twice-daily arm). Tropism switch detected before virologic failure was associated with a mean CD4-cell increase of 67 cells/mm³ among the four placebo recipients, but only 37 and 56 cells/mm³ among the 31 and 32 patients in the once-daily and twice-daily arms, respectively.

The manufacturer of maraviroc has requested FDA approval of the 150-mg twice-daily dose, based on the safety and outcomes in patients with high baseline viral loads and those with susceptibility scores of 0. Despite the stellar results in these highly experienced patients, the lingering concern about the meaning of coreceptor switch will not be allayed without longer follow-up.

— Judith Feinberg, MD

Published in AIDS Clinical Care April 2, 2007