Raltegravir (formerly MK-0518), Merck’s experimental integrase inhibitor, reduced HIV viral load to undetectable levels (below 50 copies/ml) in nearly two-thirds of highly treatment-experienced patients, according to two presentations at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles on Tuesday.
Integrase inhibitors are a new class of antiretroviral agents that target the integration step of HIV replication, in which viral genetic material is inserted into the DNA of human cells. By blocking this step in the viral life-cycle, researchers hope that integrase inhibitors will prevent the virus from reproducing and infecting more cells.
The data presented this week come from planned interim analyses from the ongoing BENCHMRK-1 and -2 studies, two identical Phase III randomised, placebo-controlled, double-blind trials involving heavily treated patients. BENCHMRK-1 included 350 participants in Europe, Asia and Peru, whilst BENCHMRK-2 included 349 patients in North and South America.
Participants in the BENCHMRK studies were resistant to all three major classes of antiretroviral drugs and had viral loads above 1,000 copies/ml. They were randomised on a two-to-one basis to receive either 400 mg raltegravir twice daily or placebo, in addition to optimised background therapy. The primary outcomes were the proportions of patients achieving viral loads below 400 and below 50 copies/ml. Data were also gathered on changes in CD4 cell count and drug safety.
Baseline characteristics were similar in the raltegravir and placebo arms of the two studies. The mean age was about 45 years, most (84-91%) were men and a majority (55-81%) were white, though BENCHMRK-2 included more people of other races/ethnicities. The mean baseline CD4 cell count was between 146 and 163 cells/mm3 and the mean baseline viral load ranged from about 30,000 to 50,000 copies/ml. About 90% had an AIDS diagnosis and the median duration of antiretroviral therapy use was about ten years.
Results from 16 weeks of follow-up were presented for all participants in the two studies, although the investigators noted that 24-week results are available for approximately 60% of patients. Both studies are scheduled to continue through 48 weeks.
After 16-24 weeks, approximately twice as many patients in the raltegravir arms achieved undetectable viral load. In the two studies combined, 77% of participants taking raltegravir had HIV RNA levels below 400 copies/ml, compared with 41-43% in the placebo arms (p < 0.001). Looking at viral loads below 50 copies/ml, the corresponding figures were 61-62% and 33-36% (p < 0.001).
Gains in CD4 cell count were also more impressive amongst the patients who received raltegravir, with a mean increase of 83 cells/mm3 in BENCHMRK-1 and 86 cells/mm3 in BENCHMRK-2. These gains were 2-3 times as large as those seen in patients who received placebo plus optimized background therapy (p < 0.001).
Researchers also presented data from analyses of patient subgroups, again combining data from both studies. Amongst those whose background regimens included both enfuvirtide (Fuzeon) or the newest protease inhibitor, darunavir (Prezista) – to which HIV is less likely to be resistant -- 98% in the raltegravir arm achieved viral suppression below 400 copies/ml, compared with 87% in the placebo group. This compared with rates of 74% and 29%, respectively, for patients not taking either of these newer drugs. For patients who had no other active drugs in their regimens, 61% in the raltegravir arm, but only 5% in the placebo arm, achieved HIV RNA levels below 400 copies/ml. In addition, participants who started with lower baseline viral loads or higher baseline CD4 cell counts had a better response to raltegravir
Raltegravir was well tolerated overall, and only a small number of participants discontinued the studies early. Side-effects – mostly mild-to-moderate – were seen with similar frequency in the raltegravir and placebo arms. The rate of serious drug-related adverse events was less than 3% across all arms.
Three times as many patients experienced virological failure on raltegravir compared with placebo (16% vs 51%). Though data are still limited, it appears that there are two distinct pathways that confer raltegravir resistance: N155H and Q148K/R/H. However, there was no indication of cross-resistance with other antiretroviral drug classes.
The researchers concluded that raltegravir demonstrated “potent and superior antiretroviral activity” compared to placebo plus optimized background therapy at 16 weeks, with “few adverse experiences leading to discontinuation.”
Raltegravir may also be an option for treatment-naive patients, having shown good antiviral activity in a study presented previously at the International AIDS Conference in Toronto last summer.
In a press conference announcing these data – and those from two studies of another new antiretroviral agent, the CCR5 inhibitor maraviroc - Dr John Mellors of the University of Pittsburgh said the results are as exciting as any since the development of HAART in the mid-1990s.